tbuckley/cabot-search huggingface dataset:
Abstract 14039: Myocardial Work Efficiency is Reduced in Nonobstructive Hypertrophic Cardiomyopathy Patients With Exercise-Induced Symptoms
Authors: Rohit Mital, Raymond B Fohtung, Dai-Yin Lu, Ramsis K Ramsis, Dwight Bibby, Nelson B Schiller, Katherine Beutner, M. R Abraham, Theodore Abraham
Journal: Circulation (2021)

Introduction: Despite normal ejection fraction, nonobstructive hypertrophic cardiomyopathy (nHCM; rest and provoked gradients &lt;30 mmHg) is associated with high rates of angina, arrhythmias and heart failure symptoms, as well as abnormalities of echo-based myocardial strain. Using Myocardial Work (MW) analysis, we investigated the potential mechanisms contributing to exercise-induced symptoms in nHCM. Methods and Results: Using validated methods (EchoPAC), longitudinal strain and non-invasive blood pressure were integrated to generate normalized left ventricular pressure curves and pressure-strain loops to derive global and segmental MW data in 14 nHCM patients with normal ejection fraction (&gt;55%) who underwent treadmill stress testing. Global myocardial work efficiency was expressed as the ratio of global constructive work over the sum of global constructive and wasted work. A total of 9 of 14 patients reported symptoms during exercise (chest pain, dyspnea, and palpitations) and this group had reduced global myocardial work efficiency compared to those without exercise-induced symptoms (85% vs 90%, respectively, p = 0.04, Figure 1). No statistical differences were noted in age, % men, maximal wall thickness, ejection fraction, E/e’ ratio, resting blood pressure, resting global strain and exercise performance between symptomatic and asymptomatic patients. Conclusions: Despite similar ventricular morphology, resting mechanics and exercise performance, nHCM patients with symptoms during exercise have worse myocardial work efficiency. Our data suggest that mechanisms potentially impacting global strain may be distinct from those affecting myocardial work efficiency. Understanding these differences may offer insights into management of exercise-induced symptoms.
CTIM-13. PHASE 1 CLINICAL TRIAL OF ONCOLYTIC VIRAL IMMUNOTHERAPY WITH CAN-2409 + VALACYCLOVIR IN COMBINATION WITH NIVOLUMAB AND STANDARD OF CARE (SOC) IN NEWLY DIAGNOSED HIGH-GRADE GLIOMA (HGG)
Authors: Patrick Wen, Laura Aguilar, Xiaobu Ye, David Reardon, Wenya Linda Bi, Pierpaolo Peruzzi, Nirav Patel, Roy Strowd, Stephen Tatter, Ian Lee, Tobias Walbert, James Snyder, Steven Brem, Arati Desai, Stephen Bagley, Nduka Amankulor, Frank Lieberman, Megan Mantica, Lenika Lopez, Susan Bell, Andrea Manzanera, Francesca Barone, Brian Guzik, Sean Lawler, Lixian Jin, William Timmer, Neeraja Danda, Serena Desideri, L Burt Nabors, Stuart Grossman, Estuardo Aguilar-Cordova, Paul Peter Tak, E Antonio Chiocca
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND CAN-2409 is a replication-deficient adenovirus that delivers HSV thymidine kinase to cancer cells, resulting in local conversion of orally administered valacyclovir into a toxic metabolite. Previously, a phase 1b/2 clinical trial of CAN-2409 combined with standard-of-care (SOC) demonstrated safety and improved survival in HGG patients. Addition of CAN-2409 to nivolumab has the potential to activate locally recruited lymphocytes and teach them to recognize tumor neoantigens, changing the ‘cold’ immunosuppressive tumor microenvironment, and synergizing with the activity mediated by immune checkpoint inhibitors. This notion is supported by preclinical experiments showing that the combination of CAN-2409 with anti-PD1 therapy was more effective than either treatment alone. METHODS This ongoing phase 1 clinical trial evaluates safety and initial efficacy of CAN-2409 combined with nivolumab and SOC in newly diagnosed HGG. CAN-2409 is injected during neurosurgery into the tumor bed, followed by 14-days of valacyclovir. Radiation starts within 8 (+/-4) days of surgery. Temozolomide is administered to MGMT-methylation positive patients only. Nivolumab is given every 2 weeks, up to 52-weeks. Deep immune profiling studies are ongoing and initial results will be available shortly. RESULTS From February 2019 to March 2021, 41 patients were enrolled and 35 were evaluable for safety from the combination of CAN-2409, nivolumab and SOC: 24 male and 11 female; 34 glioblastoma, 1 diffuse astrocytoma; 33 IDH-wildtype, 2 IDH-mutant; 15 MGMT-methylated, 20 unmethylated. Median age was 62-years (range 28-79), median KPS 90 (range 80-100). With 13 months median follow-up, no unexpected serious adverse events were observed, and 23 patients are still alive. The most frequent possibly related adverse events (&amp;gt;10%) were nausea, fatigue, fever, headache, and increased ALT. CONCLUSIONS The combination of CAN-2409 + nivolumab + SOC was well tolerated. Clinical follow-up and extensive biomarker analyses will provide a better understanding of the therapeutic potential of this approach.
Abstract 10010: Long-Term Prognostic Value of the Combination of Ahead Score and a Systemic Inflammation-Nutrition Index in Patients Admitted for Acute Decompensated Heart Failure
Authors: Takahisa Yamada, Tetsuya Watanabe, Takashi Morita, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Jun Nakamura, Kiyomi Kayama, KUMPEI UEDA, Daisuke Sakamoto, Yuto Tamura, Takeshi Fujita, Takehiro Kogame, Keisuke Nishigaki, Yuto Fukuda, Yuki Kokubu, Masatake Fukunami
Journal: Circulation (2021)

Backgrounds: Comorbidities are strongly associated with poor clinical outcome in heart failure patients (pts). AHEAD (A: atrial fibrillation; H: hemoglobin; E: elderly; A: abnormal renal parameters; D: diabetes mellitus) score has been related to clinical outcomes in acute decompensated heart failure (ADHF) pts. On the other hand, systemic inflammation plays a critical role in the outcomes of heart failure and malnutrition is also associated with poor outcome in heart failure pts. It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index х serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. We sought to investigate the prognostic value of the combination of AHEAD score and ALI in pts admitted for ADHF. Methods and Results: We studied 260 pts admitted for ADHF and discharged with survival. At the discharge, we evaluated AHEAD score (range 0-5, atrial fibrillation, hemoglobin &lt;13 mg/dL for men and 12 mg/dL for women, age &gt;70 years, creatinine &gt;130 μmol/L, and diabetes mellitus) and measured ALI. The study endpoint was cardiovascular-renal poor outcome (CVR), defined as cardiovascular death and the development of end-stage renal disease requiring renal replacement therapy. During a follow-up period of 5.1±4.2 years, 77 pts had CVR. At multivariate Cox analysis, AHEAD score and ALI were significantly associated with CVR, independently of prior heart failure hospitalization, systolic blood pressure and serum sodium level. Pts with both high AHEAD score (≥3 determined by ROC analysis: AUC 0.651[0.582-0.719]) and low ALI (&lt;35.8: AUC 0.7171[0.648-0.786]) had a higher risk of mortality than those with either and none of them (59% vs 28% vs 15%, p&lt;0.0001, respectively). Conclusion: The combination of AHEAD score and ALI would be useful for stratifying patients at risk for cardiovascular-renal poor outcome in ADHF pts.
Abstract 11187: Perceptions of Patient Heart Failure Severity and Caregiver Inflammatory Markers: Interactions with Race and Education
Authors: Megan E Mayfield, Sandra B Dunbar, Melinda K Higgins, Julie T Bidwell, Rebecca A Gary
Journal: Circulation (2021)

Background: Heart failure (HF) caregivers (CGs) may experience stress due to unpredictable patient disease trajectory. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) are reported to be elevated in dementia CGs, but less is known about HF CGs response to stress or relationships with social determinants of health such as education and race. Objective: To determine if social factors (race, education) modify the relationship between patient disease severity trajectory (NYHA class) and CG stress as measured by inflammatory biomarkers of IL-6 and hs-CRP among HF CGs. Methods: A secondary analysis was conducted using baseline data from Caregiver Opportunities for Optimizing Lifestyle (COOL) trial. Education was dichotomized into technical/high school or less versus college or post-graduate degree. Race was dichotomized as African American (AA) or White/Asian due to the low number of Asian CGs. Two-way analysis of variance tests were conducted for IL-6 and hs-CRP to test interaction effects between CG perceived NYHA class and education or race. Results: Participants (n=127) were predominantly female (n=117, 92.1%), AA (n=74, 58.3 %), and the majority (70.1%) reported a college or post-graduate education. Perceived NYHA class were reported as: I (n=32, 25.6%), II (n=31, 24.8%), III (n= 47, 37.6%), and IV (n=15, 12.0%). For hs-CRP, there was a significant interaction between race and NYHA class (p=.013). Higher hs-CRP levels were noted in class II, compared to class I or class III for AA CGs (p=.004). White/Asian CGs did not have significant hs-CRP differences between NYHA classes (p=.634). While similar trends were observed for IL-6 between race and NYHA class, it did not reach statistical significance. In the model for education and perceived disease severity, NYHA class was significant (p=.038) for hs-CRP. In the post hoc test for NYHA class, hs-CRP was highest among NYHA class II (p&lt;.02) for lower education levels. For IL-6, NYHA class was significant (p=.047); but the interaction effect with education was not significant (p=.687). Conclusions: Our findings suggest that CGs of AA race and/or lower education may experience higher stress earlier in the HF disease trajectory and may therefore benefit from targeted CG support interventions.
Abstract 13580: DNA Methylation of Skeletal Muscle Tissue in Patients With Hypertension and Diabetes Undergoing Cardiopulmonary Bypass
Authors: Ghazal Aghagoli, Naohiro Yano, Andrew M Del Re, Zhiqi Zhang, Ahmad Gheit, Ronald Phillips, Jun Feng, Alexey Fedulov, Frank W Sellke
Journal: Circulation (2021)

Introduction: Epigenomic changes may affect the condition of patients before and after surgery. The epigenome-wide DNA methylation profiling of human skeletal muscle (SKM) specimens obtained from patients undergoing cardiac surgery utilizing cardiopulmonary bypass (CPB) was examined. Hypothesis: We hypothesized that regulatory changes in SKM that develop in patients with HTN and DM include epigenetic regulation and aimed to characterize the epigenome-wide signature of these changes, both at baseline and after cardiac surgery. Methods: SKM was obtained from the internal mammary artery bed before and after termination of cardiopulmonary bypass. Specimens of patients without hypertension or diabetes (control), those with hypertension alone (BP ≥ 130), those with hypertension combined with either controlled (HbA1C &lt;=7) or poorly controlled (HbA1C &gt; 7) diabetes were examined. SKM DNA methylation was profiled via Illumina MethylationEpic arrays and analyzed by principal component analysis, cluster analysis and analysis of variance followed by network and pathway analysis. Results: DNA methylation in samples from patients with hypertension and diabetes was significantly different in 5822 loci for controlled diabetes and in 7177 loci for uncontrolled diabetes; hypertension alone produced minimal effect. These loci produced a tightly interacting network with 560 hubs and 7055 edges. These loci were associated with genes involved in pathways of IL-1, IL-12, IL-18, TNFα; IFNγ and VEGF signaling, in NF-κB and Wnt pathways, apoptosis and DNA damage response. SKM at the end of CPB revealed 282 highly significant loci or 193,567 loci with lower significance and the magnitude of the effect not exceeding 10-20%. Conclusions: Preoperatively, patients with diabetes show substantial change in SKM DNA methylation epigenome wide. Compared to diabetes, hypertension did not as substantially influence the methylome in the SKM. During surgery multiple low-grade methylation changes occur that may mask the effects of the disease; moreover in a few loci more prominent changes occur that may be part of a compensatory/regulatory response to surgery utilizing CPB.
Social inequalities and extreme vulnerability of children and adolescents affected by the COVID-19 pandemic
Authors: Aloísio Antônio Gomes de Matos, Kimberly Virginin Cruz Correia da Silva, Jucier Gonçalves Júnior, Ruan Neto Pereira Alves, Nádia Nara Rolim Lima, Monique Leite Sampaio, Cícera Janielly de Matos Cassiano, Modesto Leite Rolim Neto
Journal: Journal of the Royal Society of Medicine (2021)
RADT-21. DUAL FET PET-GUIDED SIB IN RADIOTHERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA - A PILOT STUDY
Authors: Maciej Harat, Maciej Blok, Izabela Wiatrowska, Jacek Furtak, Bogdan Małkowski
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND PET using FET is a valuable tool to determine the actual glioblastoma infiltration.The FET-PET examination can be performed using the dual-time point acquisition of FET . Infiltration defined in dual FET PET corresponds to the location and shape of the recurrence. The aim of this study was to evaluate safety and efficacy of simultaneous integrated boost based on dual FET PET combined with temozolomide TMZ for the postoperative treatment of GBM. METHODS AND MATERIALS In a prospective pilot study, 17 patients were enrolled. All patient presented an active tumor in postoperative PET imaging. The radiotherapy was performed as an FET-PET-based integrated-boost IMRT. The prescribed dose was 78 and 60 Gy (single dose 2.6 and 2.0 Gy, respectively). The progression-free survival (PFS) and overall survival (OS), toxicities and radiation necrosis rate were evaluated. RESULTS The median follow up was 37 months.Two patients were found to have uncontrolled seizures during radiation treatment and were not able to received treatment per protocol. Patients treated per protocol presented new or increased neurological deficits in 7/15 cases in a month after irradiation. In 4 patients radiation necrosis was confirmed in pathological report after re-surgery. Three patients were still alive after 26,28 and 38 months of follow up without progression and any signs of treatment related late toxicity. The 2-year survival rate was 43% in all patients treated per protocol. Median overall survival (OS) and disease-free survival (DFS) were 20 and 12 months, respectively. In a subgroup of MGMT methylated and unmethylated the median survival was 25 and 12 months. CONCLUSIONS Our dose escalation concept with a total dose of 78 Gy, based on FET-PET, have lead to promising survival results even within MGMT unmethylated subgroup. However rate of early toxicity and radiation necrosis is high.
Abstract 11309: Significance of Blood Pressure Drops in Patients Hospitalized for Acute Heart Failure: A Patient-Level Analysis of 4 Randomized Placebo-Controlled Serelaxin Trials
Authors: Johannes Grand, Kristina Miger, Ahmad Sajadieh, Lars Kober, Christian Torp-Pedersen, Georg Ertl, Jose L Lopez-sendon, Aldo P Maggioni, Olav W Nielsen
Journal: Circulation (2021)

Introduction: Hypotensive events and drops in systolic blood pressure (SBP-drop) are frequent in patients with acute heart failure (AHF). We investigated SBP-drop and associations with outcomes and whether treatment with the vasodilator serelaxin affected the association between SBP-drops and outcomes. Methods: Analyses of data from four randomized, controlled trials investigating serelaxin as an intervention in patients hospitalized with AHF. Main inclusion criteria were SBP 125-180 mmHg, pulmonary congestion, elevated NT-proBNP. SBP-drops (predefined as an SBP-value below 100 mmHg and/or a drop of 40 mmHg from baseline) were prospectively registered during the first 48 hours of hospitalization. Outcomes were a composite outcome (worsening heart failure, hospital readmission for heart failure or all-cause mortality through 14 days) and 180-day mortality. Results: Overall, 2558/11226 (23%) patients had an SBP-drop, with a median time from randomization to event of 15 (6-25) hours. In multivariable analyses, SBP-drop was associated with 180-day mortality (hazard ratio 1.21, 95% CI 1.05-1.39; p=0.009) and the composite outcome (1.29 (1.13-1.49); p&lt;0.001). Treatment-allocation interacted significantly on the relationship between SBP-drops and outcomes (p-interaction=0.003 for composite outcome, p-interaction=0.11 for 180-day mortality). In patients treated with placebo (n=5141), there was a strong association between SBP-drops and the composite outcome (HR: 1.46, 95% CI 1.19-1.79), p=0.0003), but no significant association in patients treated with serelaxin (HR 1.18, 95% CI 0.97-1.42, p=0.10) (Figure). Conclusions: SBP-drops in hospitalized patients treated for AHF is an independent risk factor for adverse short- and long-term outcomes, and its occurrence highlights the need for careful monitoring and urgent treatment. However, in patients treated with serelaxin under careful observation, SBP-drops were not associated with worse outcome.
Abstract 10644: Impact of Cardiopulmonary Bypass Surgery on Myocardial Perfusion Assessed by Ultrafast Power Doppler: A Human Proof-of-Concept Study
Authors: Minh B Nguyen, Naiyuan Zhang, Luc L Mertens, David Barron, Jerome Baranger, olivier villemain
Journal: Circulation (2021)

Introduction: Inadequate myocardial coronary perfusion is a major cause of cardiac dysfunction in several clinical settings including congenital heart disease and cardiopulmonary bypass surgery (CPB). Blood flow to the myocardium (i.e. coronary perfusion) is primarily controlled by the coronary microvasculature (vessels &lt; 500 μm) which plays a key part in coronary perfusion autoregulation. Until recently, direct quantitative coronary perfusion assessment had been infeasible due to limitations in spatial and/or temporal resolution of clinical imaging modalities. The study objective is to assess if ultrafast ultrasound-mediated power Doppler (PD) can approximate changes in myocardial perfusion in humans. Methods: We used a 6.9 MHz linear array probe connected to a programmable ultrafast ultrasound scanner (Verasonics Vantage®). We included 7 neonates with transposition of the great arteries (TGA) and acquired epicardial ultrafast acquisitions immediately before and after CPB (arterial switch operation) via open chest. The acquisitions were acquired at 2000 fps (PRF=10000Hz, 5 sources). Tissue clutter was separated from coronary signals with a sliding spatiotemporal filter. PD was measured as a representative of blood volume that scales with hematocrit. Fractional moving blood volume (FMBV) was calculated to normalize the PD signal: mean PD divided by the PD of the ventricular blood pool, a region with 100% vascular amplitude. Results and Conclusions: The FMBV post-operatively increased by a factor of two compared to pre-operative assessment, a reflection of hyperemia. These values returned to baseline on repeat assessment prior to discharge. Our findings suggest that ultrafast PD is a reliable tool in approximating changes in myocardial perfusion in the operating room and beyond. Thus, ultrafast power Doppler can be utilized to quantitatively assess the impact of CPB on coronary perfusion in humans.
Integrated Genomic Analysis Identifies UBTF Tandem Duplications As a Subtype-Defining Lesion in Pediatric Acute Myeloid Leukemia
Authors: Masayuki Umeda, Jing Ma, Benjamin J. Huang, Kohei Hagiwara, Tamara Westover, Sherif Abdelhamed, Juan Martin Barajas, Melvin Edward Thomas, Michael P Walsh, Guangchun Song, Liqing Tian, Yanling Liu, Xiaolong Chen, Pandurang Kolekar, Quang Tran, Scott Foy, Jamie L. Maciaszek, Andrew B Kleist, Amanda R. Leonti, Bensheng Ju, John Easton, Huiyun Wu, Virginia Valentine, Marc Valentine, Yen-Chun Liu, Rhonda E. Ries, Jenny L. Smith, Evan Parganas, Ilaria Iacobucci, Ryan Hiltenbrand, Jonathan Miller, Jason Myers, Evadnie Rampersaud, Delaram Rahbarinia, Michael Rusch, Gang Wu, Hiroto Inaba, Yi-Cheng Wang, Todd A. Alonzo, James R. Downing, Charles G. Mullighan, Stanley B Pounds, M. Madan Babu, Jinghui Zhang, Jeffrey E. Rubnitz, Soheil Meshinchi, Xiaotu Ma, Jeffery M. Klco
Journal: Blood (2021)
Abstract 10294: Endothelial Pannexin1-TRPV4 Signaling Regulates Pulmonary Arterial Pressure
Authors: Zdravka Daneva, Yen Lin Chen, Matteo Ottolini, Brant E Isakson, Swapnil K Sonkusare
Journal: Circulation (2021)

The pulmonary endothelial cells (EC) dilate small pulmonary arteries (PAs) and maintain low pulmonary arterial pressure (PAP). Importantly, the loss of EC function contributes to elevated PAP in pulmonary hypertension (PH). Recent studies show that Pannexin 1 (Panx1), an ATP efflux pathway at the cell membrane, is a critical regulator of endothelial function. However, the impact of endothelial Panx1 (Panx1 EC ) on PA contractility and PAP is unknown. We observed that the extracellular ATP (eATP) levels are reduced in PAs from inducible, EC-specific Panx1 -/- (Panx1 EC -/- ) mice, identifying Panx1 EC as an important ATP release pathway in PAs. Our recently published findings demonstrated that eATP dilates PAs via activation of Ca 2+ influx through endothelial transient receptor potential vanilloid 4 (TRPV4 EC ) ion channels. Therefore, we hypothesized that endothelial Panx1—eATP—TRPV4 channel signaling dilates PAs and lowers resting PAP. Apyrase (10 U/mL), an ATP hydrolyzing enzyme, reduced the activity of TRPV4 EC sparklets (individual Ca 2+ influx signals through TRPV4 EC channels) in PAs, implying a constitutive regulation of TRPV4 EC channels by ATP. The activity of TRPV4 EC sparklets was lower in PAs from Panx1 EC -/- mice than controls, identifying Panx1 EC as a novel promoter of TRPV4 EC channel activity. Pressure myography studies in PAs (~ 50 μm) from Panx1 EC -/- and TRPV4 EC -/- mice showed higher constriction to thromboxane A2 receptor agonist U46619 (1-300 nM) compared to PAs from controls. Finally, right ventricular systolic pressure was higher in Panx1 EC -/- and TRPV4 EC -/- mice compared to the respective controls. These data indicated that Panx1 EC —eATP—TRPV4 EC channel signaling lowers PA contractility and PAP. ATP is an endogenous activator of purinergic receptor signaling. Inhibition of P2Y1 and P2X receptors did not alter ATP activation of TRPV4 EC sparklets in PAs. However, P2Y2 receptor inhibition and EC-specific P2Y2 receptor deletion abolished ATP activation of TRPV4 EC sparklets. Together, these data identify a novel Panx1 EC —eATP—P2Y2R EC signaling pathway that enhances TRPV4 EC channel activity and lowers PAP. Individual elements of this pathway may provide novel therapeutic targets for treating pulmonary vascular disorders.