tbuckley/cabot-search huggingface dataset:
Abstract P420: Nano-Triciribine Reduces SARS2-CoV-2 Infection By Sequestering ACE2 And The Novel Host Factor LDLR
Authors: Jose Manuel Condor Capcha, Camila Iansen Irion, Guerline Lambert, Ahmed Chahdi, Peter Buchwald, Derek Dykxhoorn, Hamidreza Farzaneh, Sapna deo, Sylvia Daunert, Karen C Young, Lina A Shehadeh
Journal: Circulation Research (2021)

Background: People with previous CVD hospitalized for COVID-19 have elevated death rate. We reported that patients with diabetes and HF higher protein levels of the low density lipoprotein receptor (LDLR). We hypothesized that LDLR is a novel host factor for the SARS-CoV-2-Spike (S2S) protein that may be regulated by the Akt inhibitor Triciribine (TCN), a drug being tested in Phase III studies for breast cancer. We also hypothesized that nano-formulation of Triciribine (NanoTriciribine; NTCN) would enhance its efficacy and allow for intranasal delivery. Methods: Interactions between the recombinant proteins Spike-RBD (receptor binding domain), ACE2, LDLR and its ectodomains (EGFA-EFFB, C2-C5 and C2) were analyzed by binding assays and co-IP in HepG2, HK2, and 293T cells. Viral entry assays were performed with 2 S2S pseudoviruses using 293T cells + hACE2 and TMPRSS2 or Furin protease. The effect of NTCN or the LXR agonist GW-3965 on viral uptake (pseudotyped VSVΔG-GFP*S2S or chimera VSV-S2S-eGFP virus) was assessed. Akt, pAkt, ACE2, and LDLR levels were determined in 293T+hACE2 by flow cytometry. Assays were done in triplicates and 1-way-ANOVA with Tukey’s correction was used for statistics. Results: RBD protein binds modestly to the human LDLR (EC 50 :10μM) and its C2-C5 ectodomain (EC 50 :13.8μM). Co-IP revealed a novel and strong LDLR-ACE2 interaction in several human cell lines. LDLR overexpression in human cells increased the uptake of VSVΔG-GFP*S2S (FC=2.32;p&lt;0.001) and chimera virus (FC=.33; p&lt;.0001). NTCN and TCN each reduced pAkt/Akt ratio. 1μM TCN or NTCN reduced LDLR (7.2%;p&lt;.01 &amp; 15.6%;p&lt;0.0001) and ACE2 (32%;p&lt;0.05 &amp; 44.7%;p&lt;.01) cell surface expression, respectively. 1μM NTCN or GW-3965 reduced S2S viral entry by 64.2% (p&lt;.0001) and 40.7% (p&lt;.01), respectively, confirming a role for LDLR in S2S infection. In hACE2tg mice, chimera VSV-S2S caused significant lung infection as measured by qPCR, GFP expression in proximal and distal lung airway epithelial cells, and electron microscopy. Intranasal delivery of NTCN was well tolerated. Conclusions: LDLR enhanced S2S viral entry supporting the elevated COVID-19 susceptibility seen in patients with heart disease. NTCN is a promising candidate for prophylactic treatment against COVID-19.
Abstract 13602: Detection of Thermal Myocardial Injury Using the Microwave Return Loss Spectrum
Authors: Edward Yang, Vu Toan Tran, Anthony Barry, Alistair McEwan, Pierre Qian
Journal: Circulation (2021)

Introduction: Thermocouples located inside conventional ablation catheters do not measure tissue temperature nor determine thermal lesion size during cardiac catheter ablation. Hypothesis: Progressive, thermally mediated changes in tissue composition can be detected by the return loss spectrum of a microwave antenna coupling to tissue in the microwave band. Results: Return loss (RL) exhibited characteristic changes in the 1.6 to 1.7 GHz band during heating (Panel A). Heating to a temperature lethal to the myocardium (50°C) reduced the RL amplitude of the sample from baseline by 346.7% (-10.80 ± 4.430 dB, p = 0.0055). Further temperature rise restituted RL amplitude back to approximately baseline values at 64°C to 70°C (Panel B). Conclusion: The pattern of RL amplitude change in the 1.6 - 1.7 GHz microwave band may be useful for detecting lethal thermal myocardial injury and prevent overheating. This observation may have applications for monitoring cardiac catheter ablation.
Abstract 9973: Combined Inhibition of Transforming-Growth Factorβ1 and Platelet-Derived Growth Factor Receptor Improves Right Ventricular Fibrosis and Diastolic Function in Experimental Right Ventricular Pressure-Loading
Authors: John D Dauz, Kana Yazaki, Yohei Akazawa, Theo A Meister, Mei Sun, Kabir Golam, Kim A Connelly, Mark K Friedberg
Journal: Circulation (2021)

Background: Residual lesions in repaired tetralogy of Fallot and other congenital heart diseases induce chronic right ventricular (RV) pressure and/or volume loading. These activate cardiac fibroblasts (CFs) resulting in pathological myocardial remodelling, including fibrosis, contributing to eventual RV diastolic dysfunction, failure, and mortality. Transforming growth factor (TGF)β1 and platelet-derived growth factor (PDGF) are implicated in generating a hyper-fibrotic response to ventricular pressure-loading through synergistic activation and proliferation of CFs. Hypothesis: Dual TGFβ1 and PDGF inhibition will effectively reduce fibrosis in response to RV pressure-loading and thereby improve RV function. Methods: Sprague-Dawley rats underwent pulmonary artery banding (PAB) to induce RV pressure-loading or sham surgery (n=10-12/group). One-week post-PAB, rats were randomized to Tranilast (TRN), a dual TGFβ1/ PDGF inhibitor treatment, (300mg/kg/day, p.o.) or vehicle (n=10-12/group) for 5-weeks. Catheter hemodynamics were measured prior to tissue collection. Results: Preliminary hemodynamic measurements (n=8-10/group) showed similar mean RV/LV pressure ratio (PAB Vehicle 0.8±0.22 vs. PAB TRN 0.81±0.23), +dP/dT, and -dP/dT in PAB groups. PAB TRN rats demonstrated improved end-diastolic pressure (7.0±1.7mmHg vs. 8.59±3.0mmHg), tau (24.15±9ms vs. 31.26±16.5ms), and end-systolic elastance (0.084±0.038mmHg/μL vs. 0.1139±0.057mmHg/μL) compared to PAB vehicle. These were associated with reduced RV collagen deposition (6.5±2.3% vs. 10±5.1%, p&lt;0.05), hypertrophy (Fulton ratio 0.46±0.11 vs. 0.61±0.14, p=0.001), and cardiomyocyte area (921.4±131.7μm 2 vs. 1141±168.7μm 2 , p=0.003), when compared to PAB vehicle-treated controls. Immunoblotting (n=5-6/group) demonstrated reduced RV PDGFRβ expression and SMAD2/3 activation (phosphorylation), despite similar TGFβ1 levels in TRN-treated PAB rats vs. controls. Conclusion: Attenuation of TGFβR1 signalling and reduced PDGFRβ expression were associated with reduced fibrosis and hypertrophy and improved RV diastolic function. Combined inhibition of TGFβ1 and PDGF may be a relevant therapeutic target to improve RV diastolic function in RV pressure-loading.
Biosimulation Using the Cellworks Computational Omics Biology Model (CBM) Identifies Novel Biomarkers to Inform Mitoxantrone, Etoposide, and Cytarabine (MEC)-Based Combination Therapy in Refractory &amp; Relapsed Acute Myeloid Leukemia (AML) Patients
Authors: Guido Marcucci, Ansu Kumar, Michael Castro, Himanshu Grover, Vivek Patil, Aftab Alam, Humera Azam, Subrat Mohapatra, Anuj Tyagi, Pallavi Kumari, Samiksha Avinash Prasad, Prashant Ramachandran Nair, Neelesh Lunkad, Vishwas Joseph, Poornachandra G, Jyoti Chauhan, Sayani Basu, Liptimayee Behura, Adity Ghosh, Zakir Husain, Rema Mandal, Rahul K Raman, Sanjana Patel, Nirjhar Mundkur, James Christie, Michele Dundas Macpherson, Scott C Howard
Journal: Blood (2021)
Abstract 13745: Nicotine Delivered by Electronic Cigarette Vapor or Standard Cigarettes Adversely Affects Left Ventricular Systolic Function Measured by Cardiovascular Intrinsic Frequency in Rats
Authors: Rashid Alavi, Wangde Dai, Rebecca J Arechavala, Michael T Kleinman, Robert A Kloner, Niema M Pahlevan
Journal: Circulation (2021)

Introduction: Cardiovascular intrinsic frequency (IF) is a systems approach for the analysis of left ventricle (LV) function, arterial dynamics, and LV-arterial coupling. It was shown in a recent Framingham Heart Study (Hypertension 2021, 77(2):338-346) that higher values of the first IF (ω 1 ) (derived from carotid pressure waveforms) are associated with higher risk for incident heart failure and composite CVD events. Here, we examined the effect of chronic exposure to E-cigarette and standard cigarette on ω 1 in rats. Methods: Adult male and female Sprague Dawley rats were exposed to: 1) Purified air ( n =6); 2) E-cigarette vapor without nicotine ( n =6); 3) E-cigarette vapor plus nicotine (similar amount of nicotine as the standard cigarette, n =6); and 4) Standard nicotine-containing cigarette smoke ( n =9). E-cigarette was a 3rd generation type E-cigarette from VaporFi, tank model: Volt 2. Rats were placed into a nose-only exposure system. The exposures took place for 5 hours/day, 4 days/week for a total of 8 weeks. The E-liquid was a 50/50 propylene glycol/glycerin mixture with a tobacco flavor additive. After 8 weeks of exposure, the rats were anesthetized to measure the hemodynamics including invasive carotid pressure waveforms. IF parameters were computed from pressure waveforms with similar cardiac cycles. Results: There was no difference in ω 1 between purified air and E-cigarette vapor without nicotine; there was no significant difference in ω 1 between E-cigarette vapor with nicotine versus standard nicotine-containing cigarette smoke. ω 1 was significantly higher (P&lt;0.005) in the nicotine-containing groups versus the non-nicotine containing groups (Fig.1). Conclusions: Our results suggest that nicotine delivered either by standard cigarette smoke or E-cigarette vapor adversely affects the LV systolic function, and ω 1 measured from the carotid waveform alone (that can be measured non-invasively with an iPhone app), can capture these negative effects.
Venetoclax-Azacitidine As Salvage Therapy and Bridge to Allogeneic Cell Transplantation in Relapsed/Refractory AML Compared to Historical Data of the SAL Registry Study
Authors: Julia M. Unglaub, Richard F. Schlenk, Maher Hanoun, H. Christian Reinhardt, Jan Moritz Middeke, Kerstin Schäfer-Eckart, Björn Steffen, Stefan W. Krause, Christoph Schliemann, Martin Kaufmann, Mathias Haenel, Edgar Jost, Martina Crysandt, Lars Fransecky, Sabrina Kraus, Hermann Einsele, Dirk Niemann, Andreas Neubauer, Ruth Seggewiss-Bernhardt, Sebastian Scholl, Stefan Klein, Christoph Schmid, Markus Schaich, Uwe Platzbecker, Claudia D. Baldus, Martin Bornhäuser, Hubert Serve, Christoph Rollig, Michael Kramer, Elena Katelari, Maike Janssen, Caroline Pabst, Thomas Luft, Peter Dreger, Carsten Müller-Tidow, Tim Sauer
Journal: Blood (2021)
INNV-27. AN INNOVATIVE VIRTUAL MULTI-INSTITUTIONAL, MULTIDISCIPLINARY NEURO-ONCOLOGY TUMOR BOARD: THE NIH-NOB EXPERIENCE DURING THE COVID-19 PANDEMIC
Authors: James Rogers, Alvina Acquaye, Ukeme Ikiddeh-Barnes, Kaitlyn Benson, Lisa Boris, Funto Akindona, Stephen Frederico, Varna Jammula, Yeonju Kim, Michael Timmer, Orwa Aboud, Nicholas Avgeropoulos, Eric Burton, David Cachia, Kevin Camphausen, Howard Colman, Karan Dixit, Jan Drappatz, Erin Dunbar, Peter Forsyth, Edina Komlodi-Pasztor, Jacob Mandel, Eudocia Quant Lee, Surabhi Ranjan, Rimas Lukas, Michael Salacz, Matthew Smith-Cohn, James Snyder, Joseph Wooley, Huma Chaudhry, Brett Theeler, Christina Tsien, James Smirniotopoulos, John Butman, Prashant Chittiboina, John Heiss, Kareem Zaghloul, Kayla O’Donnell, Martha Quezado, Kenneth Aldape, Margarita Raygada, Terri Armstrong, Mark Gilbert, Marta Penas-Prado
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The American Academy of Neurology Institute and Society for Neuro-Oncology recommend multidisciplinary tumor board (MTB) meetings as a quality metric in neuro-oncology. With the COVID-19 pandemic resulting in travel restrictions, we expanded our existing MTB by transitioning to a virtual format that maintained our commitment to providing consultation for primary CNS tumor cases. This transition permitted participation by neuro-oncology teams from over 30 Brain Tumor Trials Collaborative (BTTC)/National Cancer Institute-Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) centers across the United States. Here, we describe results from opening our MTB remotely to these teams. METHODS We retrospectively reviewed records from remote MTB meetings held between April 2020 and March 2021. To gauge the impact of our MTB on clinical management, we administered a brief survey querying BTTC members. RESULTS Twenty-eight providers presented 41 cases during 24 virtual MTB meetings (range: 1-4 cases per meeting). Two cases (5%) were presented only for educational value. Approximately half (54%) of the cases discussed dealt with diagnosis/management of an NCI-CONNECT rare CNS tumor. During MTB discussions of the 39 cases seeking diagnosis/management recommendations, 32% received clinical trial recommendations, 10% were suggested to enroll in the NCI Neuro-Oncology Branch (NOB) Natural History Study (NCT02851706), 17% received a recommendation to obtain central neuropathology review, and 100% received recommendations for further disease management. Most BTTC survey respondents (83%) found these recommendations impactful in the management/treatment of their presented case or generally useful/informative for their clinical practice. CONCLUSION We describe the feasibility and utility of an innovative virtual multi-institutional MTB. These novel remote meetings allowed for discussion of complex neuro-oncology cases and recommendations from experts, particularly important for those with rare CNS tumors. Our study’s findings during the COVID-19 pandemic of the value of providing remote access to MTBs should apply post-pandemic.
MMP modulated differentiation of mouse embryonic stem cells on engineered cell derived matrices
Authors: Lakshmi Kavitha Sthanam, Tanusri Roy, Sejal Patwardhan, Avi Shukla, Shipra Sharma, Pradip V. Shinde, Hanuman Tulasiram Kale, P. Chandra Shekar, Kiran Kondabagil, Shamik Sen
Journal: Biomaterials (2021)
Surfing on the world stage: a narrative review of acute and overuse injuries and preventative measures for the competitive and recreational surfer
Authors: Bayan Minasian, Nigel Hope
Journal: British Journal of Sports Medicine (2021)

Surfing has rapidly grown in popularity as the sport made its debut at the Tokyo 2020 Olympic Games. Surfing injuries are becoming more relevant with the globalisation and increasing risks of the sport, but despite this, little is known about surfing injuries or prevention strategies in either the competitive or recreational surfer. Prior research demonstrates that surfers are injured at a frequency of 0.74–1.79 injuries per 1000 hours of surfing. We reviewed the literature for the incidence, anatomical distribution, type and underlying mechanism of acute and overuse injuries, and discuss current preventative measures. This review finds that skin injuries represent the highest proportion of total injuries. Acute injuries most frequently affect the head, neck and face, followed by the lower limbs. Being struck by one’s own board is the most common mechanism of injury. Non-contact acute ligament injuries have increased as surfing manoeuvres have become more acrobatic and overuse musculoskeletal injuries are highly correlated with paddling. However, there is a paucity of research for surfing injuries, and studies on overuse musculoskeletal injuries and prevention are disproportionally under-represented. Most of the prior studies are limited by small sample sizes, poor data collection methodology and geographical constraints. Further research is needed to establish preventative measures for both acute and overuse surfing injuries and to ensure the increasing popularity of surfing is met with an improved understanding of sport risks and safety. Specifically, we recommend research be prioritised regarding the efficacy of training programmes to prevent surfing-related overuse musculoskeletal injuries.
BRMP-05. Intraoperative neural tract positioning method for the maximal safe resection of tumors
Authors: Fumio Yamaguchi
Journal: Neuro-Oncology (2021)

Abstract Brain mapping is a gold standard for the surgery of tumors in eloquent area. Especially subcortical mapping is an essential method for the preservation of important neural fibers conveying motor, sensory and even higher brain functions such as language control. The efforts to estimate the fiber localizations in brain white matter sometimes result in the unprecise identification that is caused by several factors including electrical heterogeneity of brain tissues. To solve this long-standing problem, NY Tract Finder (Yamaguchi Tract Finder) was invented and has been used for intraoperative brain mappings. Now this electrode and method is used in more than 30 major hospitals in Japan, China, Taiwan and Russia. The novel and unique neural fiber positioning technique and our efforts for the maximal preservation of patients’ QOL will be introduced.
Abstract 13931: Upregulation of the AKT/mTOR Pathway in Premature Ventricular Contractions (PVC)-Induced Cardiomyopathy
Authors: Jaime Balderas Villalobos, Juana Maria de Lourdes Medina Contreras, Rafael J Ramirez, Montserrat Samsó, Alex Y Tan, Karoly Kaszala, José F Huizar, José M Eltit
Journal: Circulation (2021)

Introduction: Premature ventricular contractions (PVCs) are early ventricular depolarizations that, if frequent, can be associated with PVC-induced cardiomyopathy (PVC-CM). PVC-CM in our translational model is characterized by LV systolic dysfunction and eccentric hypertrophy. However, the mechanisms involved in this LV remodeling remain unknown. Objectives: Evaluate changes in cardiomyocyte size and sarcomere shortening, along with classical molecular pathways involved in pathological or physiological hypertrophy in the PVC-CM model. Methods: Pacemakers were implanted in healthy canines to reproduce 3 months of bigeminal PVCs (50% burden at 200-220 ms coupling interval). Isolated ventricular cardiomyocytes were electrically paced to measure sarcomere length. Formaldehyde-fixed LV sections were stained with WGA-AF633. Expression of β-MHC, ACTA1, ANP, calcineurin, AKT, mTOR, S6, 4EBP1, NFAT and their phosphorylated forms were measured by Western blot. Calcineurin activity was determined by colorimetry. Results: Cardiomyocyte area was larger in PVC group vs. sham (357.4 ± 12.9 μm 2 n= 121 vs. 271.8 + 7 μm 2 n = 161, p&lt;0.001). Time to peak sarcomere contraction was longer in the PVC group (124.9 + 25.2 ms, n=101 vs 116.2 + 27.4 ms, n=61, p&lt;0.05), whereas maximal cell shortening was similar between groups. Western blot analyses (n=6) showed significant increases in AKT expression (1 + 0.18 vs 1.6 + 0.43, p&lt;0.001), and in its downstream effectors, S6 (1 + 0.26 vs 1.46 + 0.4, p&lt;0.05) and 4EBP1 (1 + 0.3 vs 1.57 + 0.38, p&lt;0.001) in the PVC group, without changes in mTOR. On the contrary, PVC group displayed a reduction in phosphorylated AKT (Ser473, 1 + 0.14 vs 0.77 + 0.26, p&lt;0.05) and 4EBP1 (Thr37/46, 1 + 0.15 vs 0.75 + 0.1, p&lt;0.001) without changes in S6 (Ser235/236) or mTOR (Ser2448) phosphorylation. The activity and expression of calcineurin, total and phospho- NFAT, and the expression of β-MHC, ACTA1, and ANP were not different. Conclusion: The pathological calcineurin/NFAT/fetal genes pathway was unchanged in the PVC-induced eccentric hypertrophy. Thus, this hypertrophy is “atypical” characterized by an upregulation of the AKT/mTOR pathway and cellular hypertrophy, together with a paradoxical decrease in contractility and LV systolic dysfunction.
Abstract 12753: Convolutional Neural Networks Are Non-inferior To Expert Assessment For The Evaluation Of Left Ventricular Systolic Function And Mass In Chronic Heart Failure - Results From The Myovasc Study
Authors: Sven Troebs, Tony Hauptmann, David Velmeden, Jakob Soehne, Alexander Schuch, Felix Mueller, Marc Heidorn, Sebastian Göbel, Andreas Schulz, Thomas Münzel, Juergen Prochaska, Stefan Kramer, Philipp Wild
Journal: Circulation (2021)

Introduction: Convolutional neural networks (CNN) can determine markers of cardiac function and structure from echocardiographic imaging datasets. A comparison of measurement results between a CNN and conventional echocardiographic experts with regard to clinical outcome in chronic heart failure (HF) is not available. Methods: Data from the MyoVasc Cohort Study (n=3,289; NCT04064450) on chronic HF were analyzed. Comprehensive clinical phenotyping was performed during an investigation in a dedicated study center. Left ventricular ejection fraction (LVEF) and left ventricular mass (LVM) were measured by a CNN published by Zhang et al. Clinical outcome was assessed by a structured follow-up with subsequent validation and adjudication of endpoints. Results: Data from automatic and human measurements were available in 2,815 subjects with a median follow-up of 5.5 [4.2/6.6] years. The correlation of both measurements was dependent on image quality, ranging between 0.6 and 0.8. In multivariable Cox regression adjusted for age and sex, human and automated LVEF and LVM measures per changes in one standard deviation demonstrated comparable risks for all-cause mortality (LVEF: HRhuman 0.57 [0.52/0.63] vs. HRauto 0.60 [0.55/0.66]; LVM: HRhuman 1.56 [1.42/1.70] vs. HRauto 1.58 [1.43/1.76]) and for worsening HF (LVEF: HRhuman 0.55 [0.51/0.59] vs. HRauto 0.58 [0.53/0.63],; LVM: HRhuman 1.56 [1.45/1.69] vs. HRauto 1.59 [1.47/1.73]). C-indices of both prediction models did not differ significantly (P=0.19). Sensitivity analysis demonstrated no significant differences in model performance for both asymptomatic and symptomatic HF, as well as among HF phenotypes (all P&gt;0.05). Conclusions: CNN-based assessment of LVEF and LVM was non-inferior to conventional expert measurement in predicting all-cause mortality and worsening of HF. This underlines the potential of an CNN-based pipeline for automated evaluation of echocardiography in high-throughput.
Abstract 12320: Long-Term Outcomes of Open and Endovascular Management of Adult Aortic Coarctation
Authors: Philicia Moonsamy, Ami B Bhatt, Thoralf M Sundt, Doreen Defaria Yeh, Rahul Sakhuja, Jan W Boltje, Jaclyn Pagliaro, Eugene V Pomerantsev, Jordan P Bloom, Selena Li, Duke E Cameron, Matthew Eagleton, Arminder Jassar
Journal: Circulation (2021)

Objective: To compare outcomes of endovascular vs. surgical management of adult aortic coarctation (CoA). Methods: We performed a retrospective study of patients who underwent surgical vs. endovascular intervention for CoA during adulthood (age&gt;16 years) at a single institution. Results: We identified 137 adult patients with coarctation of the aorta seen between 1975 - 2019. 18/137 (13%) required no intervention for their coarctation. While 23/137 (40%) had surgical procedures and 34/137 (60%) had endovascular procedures. Surgical procedures included extra-anatomic bypass (13/23), resection of coarctation segment with interposition graft (4/23), distal hemi-arch replacement (1/23) and total arch replacement (1/23). Endovascular interventions included balloon angioplasty alone in 2/34 patients and stenting in 32/34 patients. Median age at intervention was 38 years (IQR: 30-47) in the surgical group and 36 (30-47) in the endovascular group. Patient follow up time ranged from 0-45 years with a mean follow-up of 12 years as calculated from the first intervention for CoA during adulthood. Overall survival was 96% in the surgical group and 100% in the endovascular group. There was one post-operative transient ischemic attack in the surgical group and no post-procedural complications in the endovascular group. In a Kaplan Meier analysis of freedom from re-intervention during an overall follow-up period of 45 years, surgical intervention for CoA during adulthood was superior to endovascular treatment (p=0.008). Conclusions: Although long-term survival is similar, surgical intervention for adult CoA offers superior freedom from re-intervention than endovascular treatment (p=0.008).