tbuckley/cabot-search huggingface dataset:
Abstract P383: 3D-collagen Matrix Enhanced Integrins And Matrix Metalloproteinases Expression In Cardiac Mesenchymal Cells
Authors: Senthilkumar Muthusamy, Asha V Nath, Shilpa Ajit, Anil K PR
Journal: Circulation Research (2021)

Introduction: Use of cardiac mesenchymal cells (CMCs) has been shown to improve cardiac function following myocardial infarction. Main drawback in cardiac cell therapy is the major loss of injected cells within few hours. Increase the retention of these injected cells could increase their efficacy, where cardiac patches with various cell types showed better outcome. Among, collagen patch plays lead role as a cell-laden matrix in cardiac tissue engineering. Creating a detailed understanding of how collagen matrix changes the cellular phenotype could provide seminal insights to regeneration therapy. Hypothesis: Growing CMCs in three dimensional (3D) collagen matrix could alter the expression of extracellular matrix (ECM) and adhesion molecules, which may enhance their efficacy. Methods: The bovine type I collagen was chemically modified and solubilized in culture medium with photo-initiator. The mouse CMCs were isolated and resuspended in collagen solution, printed using 3D bioprinter and UV-crosslinked to form 3D-CMC construct. The 3D-CMC construct was submerged in growth medium and cultured for 48h and analyzed for the expression of ECM and adhesion molecules (n=5/group). CMCs cultured in regular plastic tissue culture dish was used as control. Results: RT profiler array showed changes in the ECM and adhesion molecules expression, specifically certain integrins and matrix metalloproteinases (MMPs) in CMCs cultured 3D collagen construct compared to 2D monolayer. Subsequent qRT-PCR analysis revealed significant (p&lt;0.01) upregulation of integrins such as Itga2 (2.96±0.13), Itgb1 (3.18±0.2) and Itgb3 (2.4±0.27) and MMPs such as MMP13 (37.2±3.36), MMP9 (5.23±1.06) and MMP3 (7.14±2.07). Western blot analysis further confirmed significant elevation of these integrins and matrix metalloproteinases at protein level. Collagen encapsulation did not alter the expression of N-cadherin in CMCs, which is a potential mesenchymal cadherin adhesion molecule. Conclusion: Integrin αβ heterodimers transduce signals that facilitate cell homing, migration, survival and differentiation. Similarly, MMPs plays vital role in cell migration and proliferation. Our results demonstrate that the 3D-collagen Niche enhances the expression of certain integrins and MMPs in CMCs. This suggest that the efficacy of CMCs could be magnified by providing 3D architecture with collagen matrix and further in vivo experiments would reveal functional benefits from CMCs for clinical use.
Abstract 13414: Studying Sonoporation-Induced Drug Payload Penetration Beyond the Blood-Brain Barrier Using Multi-Cellular Human Brain Spheroids
Authors: Anurag N Paranjape, Leonardo D’Aiuto, Wenxiao Zheng, Thiruganesh Ramasamy, Xucai Chen, Flordeliza S Villanueva
Journal: Circulation (2021)

Introduction: Ultrasound-targeted microbubble cavitation ( UTMC ) facilitates delivery of cell-impermeant drugs across the endothelial barrier, such as the blood brain barrier ( BBB ) . Using cultured endothelial cell ( EC ) monolayers, we reported that UTMC causes sonoporation and inter-endothelial gaps, which may mediate vascular hyperpermeability, although mechanisms are incompletely understood. Further, the effects of UTMC on extravascular cells, and extent of payload penetration are unknown, as the monolayer does not recapitulate the 3D multicellular environment. Here, we established a 3D multicellular human brain spheroid model to study UTMC bioeffects and underlying mechanisms. Methods: Spheroids were generated using neurons and astrocytes derived from human iPSCs, primary human brain- microglia, ECs and pericytes, and placed in a water tank with lipid microbubbles ( MBs ). Ultrasound (1 MHz frequency, 250-500 kPa peak negative pressures, 10 μs pulse duration, 10 ms pulse interval) was delivered for 20 s and spheroids were immediately collected. Immunostaining was used to localize cell types; propidium iodide (PI) uptake to mark sonoporation; calcein-AM and sytox to detect cell viability; and Texas red dextran (TRD) (10 kDa) to quantify permeability, using confocal microscopy. Results: Immunostaining showed ECs and pericytes at the spheroid periphery, with high expression of membranous ZO-1. BBB functionality was confirmed with histamine treatment, which increased permeability to TRD (28.8% increase in TRD mean intensity, p =0.0015). Interestingly, PI uptake (sonoporation) occurred in cells beyond the BBB. TRD penetrated up to ~100 μm beyond the BBB upon UTMC (12.2% increase). Inhibition of endothelial nitric oxide synthase with L-NAME reduced UTMC-induced TRD penetration (19% decrease, p =0.0458). Conclusions: In this novel 3D human brain spheroid model with intact BBB, UTMC caused nitric-oxide dependent BBB breach. Moreover, this is the first report of UTMC causing “remote” sonoporation of cells not in direct contact with MBs, which bears further study. Our model allows the study of mechanisms mediating UTMC efficacy for targeted delivery of drugs across the endothelial barrier, which should facilitate its clinical translation.
Abstract 10151: Association of Polygenic Risk Scores for Pre-Eclampsia and Blood Pressure with Hypertensive Pregnancy Disorders
Authors: Jouko Nurkkala, Anni Kauko, Hannele Laivuori, Saarela Tanja, Jaakko Tyrmi, Susan Cheng, Jenni Aittokallio, Teemu Niiranen
Journal: Circulation (2021)

Introduction: Blood pressure (BP) is a known risk factor for pre-eclampsia. We examined whether a BP-polygenic risk score (PRS) as compared with a pre-eclampsia-PRS, could also predict gestational hypertension (GHT), pre-eclampsia, and eclampsia. Methods: Our study sample included 116434 genotyped, previously-pregnant participants of the FinnGen cohort who were followed up between 1969-2019. PRSs for systolic BP and pre-eclampsia were derived using UK Biobank summary statistics for &gt;1.1 million single nucleotide polymorphisms. Results: We observed 6561 cases of GHT, 5263 cases of pre-eclampsia, and 385 cases of eclampsia. As shown in the Figure, we observed that the BP-PRS was associated with GHT (multivariable-adjusted HR for 1-SD increase in PRS, 1.40; 95% CI, 1.36-1.43; p=9x10 -160 ), pre-eclampsia (HR, 1.26 (95% CI 1.23-1.30, p=1.6x10 -63 ) and with eclampsia (HR, 1.29 (95% CI, 1.16-1.42, p=8.1x10 -7 ), respectively. The pre-eclampsia-PRS was also associated with GHT (HR, 1.09; 95% CI 1.07-1.12, p=1.0x10 -12 ) pre-eclampsia (HR, 1.09; 95% CI, 1.06-1.12, p=2.2x10 -10 ) and eclampsia (HR, 1.12, 95% CI, 1.02-1.24, p=0.023), although these associations were more modest. The model c-statistic for incident pre-eclampsia increased from 0.544 to 0.591 (95% CI for difference, 0.022-0.034, p&lt;1x10 -300 ) when BP-PRS was included in a model with pre-eclampsia-PRS. Conclusions: Our study confirms that the increased risks for developing GHT, pre-eclampsia and eclampsia are strongly associated with genetic factors related to BP. A BP-PRS seems to be an even stronger predictor of hypertensive pregnancy complications than a pre-eclampsia-PRS. Our results suggest common pathways for the development of these diseases that need to be further investigated.
Effect of the Neddylation Inhibitor Pevonedistat on Normal Hematopoietic Stem Cell Subsets and Immune Cell Composition
Authors: Fatemeh Majidi, Oumaima Stambouli, Ron-Patrick Cadeddu, Simon Kai Brille, Jasmin Ewert, Ulrich Germing, Robert Zeiser, Bernd Giebel, Norbert Gattermann
Journal: Blood (2021)
Retrospective Review of the Safety and Efficacy of High-Dose Methotrexate for Prevention of CNS Relapse in Diffuse Large B-Cell Lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)
Authors: Lisa Y Law, Mrinal Dutia, Ryan Stevenson, Melanie Lau, Timothy Mok, Khoan Vu, Aye Min Soe, Alfredo R. Lopez, Sachdev Thomas, Hyma T. Vempaty, Aruna Gavini, Bijay Nair
Journal: Blood (2021)
Abstract 11480: Machine Learning Discovers a Prediction Model for Contractile Function of Circulatory Death Donor Hearts Based on Microvascular Flow Shifts During Ex-Situ Hypothermic Cardioplegic Machine Perfusion
Authors: Lars Saemann, Matthias Kohl, Gábor Veres, Sevil Korkmaz-Icoez, Matthias Karck, Andreas Simm, Folker Wenzel, Gabor Szabo
Journal: Circulation (2021)

Introduction: Hearts, procured from circulatory death donors (DCD) are predominantly resuscitated and maintained ex-vivo by machine perfusion (MP) with warm donor blood. Currently, DCD-heart function is evaluated by the course of lactate and by visual inspection. We have shown in an experimental research series that MP with the cardioplegic, crystalloid Custodiol-N solution is superior to blood perfusion to maintain DCD-hearts. However, no method has been developed yet to predict contractile function of DCD-hearts after continuous cardioplegic MP. Hypothesis: We hypothesize that the shift of microvascular flow during continuous MP with a cardioplegic preservation solution predicts contractile function of DCD-hearts. Methods: In a pig model, DCD-hearts were harvested and maintained by MP with hypothermic, oxygenated Custodiol-N solution for 4 h while myocardial microvascular flow (LDF) was measured by Laser-Doppler-Flow technology in the left ventricular wall. Subsequently, hearts were perfused with blood for 2 h and left ventricular contractility was measured with a balloon catheter after 30 and 120 min. Various novel parameters which represent the LDF-shift, were computed. Bivariate prediction models based on two combined LDF-shift parameters were identified based on machine learning algorithms. Results: Highest r 2 for ESP was 0.77 (p=0.027), for dp/dt max was 0.73 (p= 0.037) and for dp/dt min was 0.75 (p=0.032) after 30 min of reperfusion. After 120 min of reperfusion, highest r 2 for ESP was 0.81 (p=0.016), for dp/dt max was 0.90 (p=0.004) and for dp/dt min 0.58 (p=0.115). Identical prediction models were identified for dp/dt max and for dp/dt min at both time points of reperfusion. Lactate remained constant during MP and therefore was unsuitable for prediction. Conclusions: Contractile function of DCD-hearts after continuous MP with a cardioplegic preservation solution can be predicted by the shift of LDF during MP.
Abstract 10738: Comparative Outcomes of Sacubitril/Valsartan Use Among Medicare Beneficiaries NaïVe to Renin-angiotensin System Inhibitors and Hospitalized with Heart Failure
Authors: Vanessa Blumer, Sujung Choi, Stephen J Greene, N. Chantelle Hardy, Melissa A Greiner, Anthony Carnicelli, Xian Shen, Steven J Lippmann, Pamela Peterson, Larry A Allen, Gregg C Fonarow, Robert J Mentz, Emily C OBrien
Journal: Circulation (2021)

Introduction: Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared to ACE inhibitors; however, comparative effectiveness data on post-discharge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. Methods: We analyzed Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF in the Get With The Guidelines Heart Failure registry between 10/2015 and 6/2019, had Part D prescription coverage, and were not on RASi therapy 6 months prior to hospital admission. We examined associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30 days and 1 year after discharge using overlap weighted Cox proportional hazards models. The primary endpoint was “home-time”, defined as days alive and out of any healthcare institution. Secondary endpoints included mortality and rehospitalization. Results: Among 3,572 patients with HFrEF and naïve to RASi therapy, 290 (8.1%) were prescribed sacubitril/valsartan at hospital discharge. After adjusting for baseline patient characteristics, patients prescribed sacubitril/valsartan had greater home-time (parameter estimate [PEs] 27.0, 95%CI 12.4-41.6, p&lt;0.001) and lower all-cause mortality (HR 0.74, 95%CI 0.6-0.9, p=0.004) compared with patients not on sacubitril/valsartan. Prescription of sacubitril/valsartan was not significantly associated with all-cause (HR 0.87, 95%CI 0.7-1.0, p=0.10) or HF rehospitalization (HR 0.87, 95%CI 0.7-1.1, p=0.19) (Figure) Conclusions: In this contemporary, real-world population of RASi-naïve patients with HFrEF, initiation of sacubitril/valsartan at discharge was associated with greater home-time and improvements in overall survival similar to that seen in randomized trials. These findings support recent expert consensus recommendations endorsing a direct-to-sacubitril/valsartan therapeutic approach among RASi-naïve patients.
A Pilot Plant-Based Dietary Intervention in Overweight and Obese Patients with Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma- the Nutrition Prevention (NUTRIVENTION) Study
Authors: Urvi A Shah, Daniel Alicea, Peter A. Adintori, Miranda Burge, Jenna Blaslov, Andriy Derkach, Sham Mailankody, Neha Korde, Carlyn Tan, Malin Hultcrantz, Sydney X. Lu, Dhwani Patel, Hani Hassoun, Anita D'Souza, Sergio A Giralt, Neil Iyengar, Ola Landgren, Marcel van den Brink, Alexander Lesokhin
Journal: Blood (2021)
CTNI-03. EXTENDED BENEFITS IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA THAT CONTINUOUSLY RECEIVE TOCA FC AFTER TOCA 511 TREATMEN
Authors: Tobias Walbert, Denise Damek, L Martinez Nina, David Piccioni, Samuel Singer, Timothy Cloughesy
Journal: Neuro-Oncology (2021)

Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) constructed with a codon-optimized yeast cytosine deaminase (CD) gene. Toca 511 infects cancer cells, and stably delivers CD gene whose protein product converts courses of the prodrug TocaFC (5-fluorocytosine) into 5-fluorouracil (5-FU). Several phase 1 studies and a phase 2/ 3 clinical study tested Toca511 in combination with TocaFC in patients undergoing planned resection for recurrent glioblastoma (rGBM) or anaplastic astrocytoma (rAA). The last trial was completed in 2019, and although the Phase 2/3 study did not meet the primary objective, patients who appeared to benefit from the treatment elected to continue TocaFC through an expanded access or compassionate use pathway. Seven patients continued on treatment: 3 men and 4 women; 5 with rGBM, 2 with rAA. Duration of treatment with TocaFC ranges from 29 months to 7 years and 5 months (average 49.2 months). Six patients who are still on active treatment with TocaFC have either stable disease or complete response. TocaFC is well tolerated in these patients, typical side effects include diarrhea. Some patients with rGBM or rAA appear to benefit from extended TocaFC treatment after Toca511. Individual cases will be discussed.
CSIG-23. ELONGATION CONTROL OF mRNA TRANSLATION DRIVES GROUP 3 MEDULLOBLASTOMA ADAPTATION TO NUTRIENT DEPRIVATION
Authors: Alberto Delaidelli, Gian Luca Negri, Betty Yao, Que Xi Wang, Yue Zhou Huang, Christopher Hughes, Gabriel Leprivier, Poul Sorensen
Journal: Neuro-Oncology (2021)

Abstract Group 3 affiliation and MYC genetic amplification are associated with poor life expectancy and substantial morbidity in children suffering from medulloblastoma (MB). However, the high metabolic demand induced by MYC-driven transformation sensitizes MYC-overexpressing MB to cell death under conditions of nutrient deprivation (ND). Additionally, MYC-driven transformation is known to promote mitochondrial oxidative phosphorylation (OXPHOS). We previously reported that eukaryotic Elongation Factor Kinase 2 (eEF2K), the master regulator of mRNA translation elongation, promotes survival of MYC-overexpressing tumors under ND. Interestingly, eEF2K is overexpressed in MYC-driven MB and our preliminary proteomics data highlight large-scale alterations in OXPHOS components affecting eEF2K deficient MB cells. We therefore hypothesized that eEF2K activity is required for the selective translation of mRNAs needed for efficient OXPHOS, and for the progression of MYC-driven MB. We pefrormed Multiplexed enhanced Protein Dynamic Mass Spectrometry in eEF2K knockdown MYC-overexpressing D425 MB cells to identify mRNAs selectively translated upon eEF2K activation. Messenger RNAs encoding multiple (9 out of 10 detected) components of the mitochondrial OXPHOS pathway are selectively translated upon eEF2K activation. Inactivation of eEF2K by genetic KO leads to the disassembly of electron transport chain (ETC) complexes I-IV without affecting mRNA levels of their respective components. Consistently, eEF2K KO MB cells display decreased mitochondrial membrane potential and 20% increased proton leak thorough the mitochondrial membrane. In addition, eEF2K inactivation results in increased Group 3 MB cell death under ND and doubles survival of MB bearing mice fed with calorie restricted diets (p&amp;lt; 0.05). Control of mRNA translation elongation by eEF2K is critical for mitochondrial ETC complex assembly and efficient OXPHOS in MYC-overexpressing MB, likely representing an adaptive response by which MYC-driven MB cells cope with acute metabolic stress. Future therapeutic studies will aim to combine eEF2K inhibition with caloric restriction mimetic drugs as eEF2K activity appears critical under metabolic stress conditions.
Abstract 14267: Comprehensive STEMI Protocol Enhances Process and Care Metrics in Patients With In-Hospital STEMI
Authors: Nicholas Kassis, Raunak Nair, Anirudh Kumar, Chetan Huded, Michael Johnson, Kathleen A Kravitz, Grant W Reed, Amar Krishnaswamy, Venu Menon, A M Lincoff, Samir R Kapadia, Umesh N Khot
Journal: Circulation (2021)

Introduction: Patients who experience in-hospital ST-elevation myocardial infarction (iSTEMI) represent a uniquely high-risk cohort owing to delays in diagnosis and time to reperfusion as well as substantially increased mortality. Quality initiatives aimed at improving the care of this vulnerable, yet understudied population are needed. Methods: This study included consecutive patients with iSTEMI treated with percutaneous coronary intervention (PCI) between 01/01/2011-07/15/2019 at a single, tertiary referral center. A comprehensive iSTEMI protocol (CSP) was implemented on 7/15/2014, incorporating: (1) nursing chest pain protocol, (2) improved electronic access to ECG images, (3) checklist for initial triage and management, (4) 24/7/365 catheterization lab readiness, and (5) radial-first PCI approach. Key metrics and outcomes were compared before and after CSP implementation. Results: Among 132 total subjects, the post-CSP cohort (n=84) were older with more males and active smoking relative to the pre-CSP cohort (n=48). After CSP adoption, we observed significant reductions in median door-to balloon time (D2BT) from 107 minutes to 64 minutes (p&lt;0.001), median fluoroscopy dose from 1.6 Gy to 1.2 Gy (p=0.04), and mean contrast load from 181mL to 148mL (p=0.02), with simultaneous increases in goal D2BT from 39% to 74% of patients (p&lt;0.001) as well as radial use from 15% to 70% (p&lt;0.001). Despite a numerical decrease in in-hospital mortality after CSP application from 17% to 10% (p=0.35), no significant differences were found in all outcomes including 30-day and 1-year mortality between groups. Conclusion: The implementation of a CSP was associated with marked improvements in critical process and care metrics among vulnerable patients who experience STEMI while hospitalized. Interestingly, these benefits failed to improve short or long-term outcomes including mortality, highlighting the underlying high-risk nature of this population.
PATH-47. THE 2016 WHO CLASSIFICATION AND IT'S CLINICAL IMPACT: THE LEEDS TEACHING HOSPITALS NHS TRUST EXPERIENCE
Authors: Neeraj Kalra, Zhuowen Geng, Helen Bailey, Alna Dony, Aruna Chakrabarty, Paul Roberts, Ryan Mathew
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION In 2016 the WHO Classification of Tumours of the Central Nervous System was updated to include molecular testing, in addition to the previous standard histological methods; producing a final integrated diagnosis. Although molecular information can guide treatment and aid in prognostication, it adds a significant workload to pathology and genetic testing services. Delayed diagnosis can also add anxiety to patients, at an already traumatic time. AIMS: To determine if final integrated diagnoses, for patients undergoing neurosurgery for CNS tumours, is being provided in an appropriate time frame, and whether it changes clinical management. METHODS All patients &amp;gt;16 years at the time of surgery with a histopathologically-confirmed CNS tumour were identified from 2016-2020. A retrospective analysis of the time taken to produce an integrated histological diagnosis took place, using the date of surgery and date of verified final integrated report being the first and last data points respectively. Data were collected by accessing electronic and paper health records, and local databases. Changes in clinical management between the initial histology result and the final integrated diagnosis were classified as no change or a major change. RESULTS 1390 surgical procedures for CNS pathology were identified between 2016-2020, producing 361 final integrated diagnosis reports. 64 (18%) of these reports resulted in a major change in clinical management when compared to the initial histology report. The turn-around time for initial histology from date of surgery was a mean of 9 days and a mean of 34 days for the final integrated diagnosis. CONCLUSIONS The integrated diagnosis is essential for providing the gold standard of treatment for patients, although for the majority of patients it does not change their clinical management. Further study and discussion is required about the role of the final integrated diagnosis in the management of patients with CNS tumours.