tbuckley/cabot-search huggingface dataset:
Abstract MP220: Identification And Functional Characterization Of Exosomal Bk Channels
Authors: Shridhar Sanghvi, Julie A Dougherty, Parker Evans, Divya Sridharan, Devasena Ponnalagu, Kalina Szteyn, Vishnu Sundaresan, Mahmood Khan, Harpreet Singh
Journal: Circulation Research (2021)

Extracellular vesicles (EVs) specifically exosomes are important in mediating intracellular communications, and are capable of transferring genetic information between cells. Exosomes are used as a drug delivery vehicle to carry cargo for targeted therapy and have emerged as one of the most promising candidate for treating cardiovascular diseases. Exosomes get packaged inside the cell, excise out to the extracellular environment, and deliver the cargo to the target cells. However, the precise mechanism of how exosomes handle the differential ionic environment and the physiological role of their ion channels is not determined. Given that potassium (K + ) ions has the largest gradient, we focused on identifying the presence and physiological relevance of K+ channels in exosomes. Using the in silico approach, several ion channel candidates were identified, the most prominent ion channel being large conductance Ca 2+ and voltage-activated potassium channel (BK). To record BK in exosomes, we incorporated planar bilayers and a novel electrophysiology approach called near field electrophysiology (NFE), as the canonical patch-clamp methods are not feasible due to the size of EVs. Our NFE indicates a presence of K + channels in intact exosomes and 45% of them are sensitive to IbTX. Since IbTX specifically blocks, BK channels, we estimated 2 functional channels (single-channel conductance of 300 pS with 50% open probability) in a single exosome. Plasma-derived exosomes from BK +/+ and BK -/- mice subjected to differential K + gradient indicated that functional BK channels exist in exosomes, and help in maintaining their structural integrity. Furthermore, plasma derived exosomes from BK +/+ mice showed cardioprotection from ischemia-reperfusion injury whereas exosomes from BK -/- mice did not. Thus, the presence of BK determines the packaging as well as cardioprotective function of exosomes. Overall, the study for the first time indicate a presence of functional ion channel (BK) in exosomes which plays a role in protecting cells and heart against ischemia and reperfusion injury.
NCOG-19. PROGNOSTIC FACTORS IN ELDERLY PATIENTS WITH GLIOBLASTOMA: A RETROSPECTIVE INSTITUTIONAL SERIES OF 160 PATIENTS
Authors: Alessia Pellerino, Francesco Bruno, Edoardo Pronello, Francesca Mo, Federica Franchino, Roberta Rudà, Riccardo Soffietti
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Glioblastoma (GBM) prevails in elderly patients, who often suffer from other comorbidities that may affect the outcome. The aim of the study was to investigate clinical characteristics, comorbidities, and treatment-related complications that may impact the outcome of elderly patients with GBM. PATIENTS AND METHODS In this institutional retrospective study, we included GBM patients ≥ 65 years diagnosed with glioblastoma from 2015 to 2020. We retained information about comorbidities according to Charlson Comorbidity Index (CCI), Karnofsky prognostic score (KPS), MGMTp methylation, and clinical complications during treatment or follow-up. RESULTS We included 160 patients. Median age was 72 years (65-88). Median time of follow-up was 9.25 months. Median progression-free survival (mPFS) and overall survival (mOS) were 5.84 and 9.67 months. In a multivariate analysis, factors affecting survival were: KPS after surgery ≥ 70 (mPFS: HR 0.24, 0.13-0.44; mOS: HR 0.43, 0.24–0.76. 95% CI), partial vs gross total resection (mPFS: HR 2.15, 1.23–3.77; mOS: HR 2.61, 1.34–5.07. 95% CI), MGMTp methylation (mPFS: HR 0.35, 0.22–0.55; mOS: HR 0.37, 0.24–0.76. 95% CI), and complications after surgery (mPFS: HR 2.52, 1.39–4.55; mOS: HR 2.96, 1.63–5.40. 95% CI). Conversely, age and CCI were not significantly correlated with prognosis. CONCLUSIONS For elderly patients with GBM, CCI does not seem to predict the outcome. Other factors such as extent of surgery, MGMTp methylaton, postoperative KPS, and clinical complications after surgery retain a significant prognostic importance. Further studies are needed to standardize clinical prognostic scales specific for elderly GBM patients.
NIMG-26. IMPROVING THE GENERALIZABILITY OF DEEP LEARNING FOR T2-LESION SEGMENTATION OF GLIOMAS IN THE POST-TREATMENT SETTING
Authors: Jacob Ellison, Francesco Caliva, Pablo Damasceno, Tracy Luks, Marisa LaFontaine, Yan Li, Valentina Pedoia, Javier Villanueva-Meyer, Janine Lupo
Journal: Neuro-Oncology (2021)

Abstract Although current advances for automated glioma lesion segmentation and volumetric measurements using deep learning have yielded high performance on newly-diagnosed patients, response assessment in neuro-oncology still relies on manually-drawn, cross-sectional areas of the tumor because these models do not generalize to patients in the post-treatment setting, where they are most needed in the clinic. Surgical resections, adjuvant treatment, or disease progression can alter the characteristics of these lesions on T2-weighted imaging, causing measures of segmentation accuracy, typically measured by Dice coefficients of overlap (DCs), to drop by ~15%. To improve the generalizability of T2-lesion segmentation to patients with glioma post-treatment, we evaluated the effects of: 1) training with different proportions of newly-diagnosed and treated gliomas, 2) applying transfer learning from pre- to post-treatment domains, and 3) incorporating a loss term that spatially weights the lesion boundaries with greater emphasis in training. Using 425 patients (208 newly-diagnosed, 217 post-Tx, with 25 treated patients withheld as a test set) and a top-performing model previously trained on newly-diagnosed gliomas, we found that DCs increased by 10% (to 0.84) then plateaued after including ~25% of post-treatment patients in training. Transfer learning (pre-training on newly-diagnosed and finetuning with post-treatment data) significantly improved Hausdorf distances (HDs), a measure more sensitive to changes at the lesion boundaries, by 17% after including 26% post-treatment images in training, while DCs remained similar. Although modifying our loss functions with boundary-weighted penalizations resulted in comparable DCs to using standard DC loss, HD measures were further reduced by 26%, suggesting that HDs may be a more sensitive metric to subtle changes in segmentation accuracy than DCs. Current work is evaluating their utility in providing accurate volumes for real-time response assessment in the clinic using workflows that have recently been deployed on our clinical PACs system.
Abstract 14453: Risk of Atrial Fibrillation (AF) With Radiation Therapy Compared to Known Drugs Causing AF: Data From the FDA Adverse Event Reporting System, a Pharmacovigilance Database
Authors: Malak Modi, Sahith Reddy Thotamgari, Paari Dominic
Journal: Circulation (2021)

Introduction: Even though some studies have implicated radiation therapy (RT) as a risk factor for atrial fibrillation (AF), the association between RT and AF remains controversial. Hypothesis: To estimate the risk of AF associated with RT and compare it with dobutamine, flecainide, propafenone, ibrutinib and adenosine - the most common drugs causing AF. Methods: The US Food and Drug Administration’s Adverse Event Reporting System (FAERS) was queried for “Atrial fibrillation (AF)” secondary to “radiation therapy”, “Dobutamine”, “dobutamine hydrochloride”, “dobutamine hydrochloride in dextrose”, “flecainide”, “flecainide acetate”, “propafenone”, “propafenone hcl”, “propafenone hydrochloride”, “propafenone hydrochloride sr”, “ibrutinib” and “adenosine” and all other drugs on May 25, 2021. Disproportionality signal analysis was performed by calculating the reporting odds ratio (ROR) with its 95% confidence interval (CI). The ROR was considered significant when the lower limit of the 95% CI was &gt;1.0. Results: FAERS database has a total of 22,002,078 AE reported till May 25, 2021. The ROR (95% CI) for AF due to RT versus all other drugs in FAERS was 3.9 (2.9 to 5.3) signifying disproportionately increased reporting. ROR (95%CI) for AF due to dobutamine, flecainide, propafenone, ibrutinib and adenosine was 18.2 (15.6 to 21.3), 19.0 (17.0 to 21.2), 35.9 (32.5 to 39.7), 16.6 (15.9 to 17.4) and 10.0 (7.4 to 13.6) respectively. Conclusions: While there is significantly higher reporting of AF with RT, this risk is lower when compared to the most common causes of drug induced AF.
Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
Authors: Janne Lehtiö, Taner Arslan, Ioannis Siavelis, Yanbo Pan, Fabio Socciarelli, Olena Berkovska, Husen M. Umer, Georgios Mermelekas, Mohammad Pirmoradian, Mats Jönsson, Hans Brunnström, Odd Terje Brustugun, Krishna Pinganksha Purohit, Richard Cunningham, Hassan Foroughi Asl, Sofi Isaksson, Elsa Arbajian, Mattias Aine, Anna Karlsson, Marija Kotevska, Carsten Gram Hansen, Vilde Drageset Haakensen, Åslaug Helland, David Tamborero, Henrik J. Johansson, Rui M. Branca, Maria Planck, Johan Staaf, Lukas M. Orre
Journal: Nature Cancer (2021)
Abstract 13997: Thirty-Day Readmissions Rates and Causes Among Patients After Heart Transplant: Insights From the Nationwide Readmissions Database
Authors: Amandeep Goyal, Prakash Acharya, Suveenkrishna Pothuru, Shubham Lahan, Sagar Ranka, Tarun Dalia, Siva Taduru, Andrew J Sauer, Nicholas Haglund, Andrija Vidic, Zubair Shah
Journal: Circulation (2021)

Introduction: Heart transplantation (HT) is a treatment of choice for many patients with advanced heart failure who continue to deteriorate despite optimal medical therapy. Data on patient characteristics, predictors, and readmission rates after HT is limited. We sought to evaluate the causes and predictors of the 30-day readmission rate among HT patients. Methods: Using the Nationwide Readmission Database, we included adult patients (≥18 years old) who underwent HT between January 2016 to November 2018. Patients with dual organ transplants were excluded from the study. Thirty-day readmission rates, causes, and predictors of readmission were assessed. Results: We analyzed 7386 patients who underwent HT and discharged alive during the years 2016 to 2018. The mean age was 53.35 ± 12.97 years and 73% were males. The 30-day readmission rate was 22.4% (n=1647). Heart transplant rejection/failure was the main cause of readmission (16.3%) followed by systemic infections (13.2%), post-procedure transplant complications (10%), acute kidney injury (6.3%), and procedure-related wound infection (4.2%) (Fig 1A) . Using multivariate logistic regression the risk of 30-day readmission was higher in patients with high comorbidity burden if Elixhauser score &gt; 14 (OR 1.41: 95% CI 1.10-1.79) and in patients who have a length of stay &gt; 30 days during index admission (OR 1.18: 95% CI 1.01-1.39). Female gender was also found to be an independent predictor of readmission (OR 1.33: 95% CI 1.09-1.61) (Fig 1B) . Conclusions: Readmission rate is high in orthotopic heart transplant patients and is driven mostly by graft rejection/failure, infections, and post-procedure-related complications. Pre-transplant identification of high-risk patients will help in improving outcomes.
Abstract 9948: Increased Soluble Programed Cell Death Ligand-1 is Associated with Acute Coronary Syndrome
Authors: Koichiro Fujisue, Shuhei Miyazaki, Takashi Komorita, Koichi Egashira, Eiichiro Yamamoto, Daisuke Sueta, Fumi Oike, Hiroki Usuku, Seiji Takashio, Satoshi Araki, Kenichi Matsushita, Kenichi Tsujita
Journal: Circulation (2021)

Background: Programmed cell death (PD)-1 and its ligand (PD-L1) plays crucial roles in T-cell tolerance as immune checkpoint. Previous studies reported that increased serum levels of soluble PD-L1 (sPD-L1) reflect myocardial and vascular inflammation. However, little is known about the clinical relationship between sPD-L1 and acute coronary syndrome (ACS). We investigated the relation of sPD-L1 and ACS. Methods: We prospectively measured serum levels of sPD-L1 using a commercially available enzyme-linked immunosorbent assay kit in patients with coronary artery disease (CAD) and continuous non-CAD admitted to Kumamoto University Hospital between December 2017 and June 2019. All malignant diseases, patients who underwent hemodialysis, active collagen diseases, and severe infectious diseases were excluded. Results: Totally, 446 CAD patients [ACS, n=124; chronic coronary syndrome (CCS), n=322] and 24 non-CAD patients were analyzed. The levels of sPD-L1 were significantly higher in patients with ACS than those both with non-CAD and CCS {ACS, 188.7 (111.0-260.8) pg/mL, P&lt;0.001 vs. non-CAD [83.5 (70.8-130.4) pg/mL]; and P=0.009 vs. CCS [144.2 (94.8-215.5) pg/mL], respectively}. Univariate logistic regression analysis identified that hypertension, dyslipidemia, current smoking, usage of aspirin, beta blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and the levels of low density-lipoprotein cholesterol, high sensitive C-reactive protein, and high sensitive troponin-T levels were significant factors associated with ACS. sPD-L1 was also significantly associated with ACS [odds ratio (OR): 1.003, 95 % confidence interval (CI): 1.002-1.005, P=0.001]. Multivariable logistic regression analysis with nine significant factors identified from the univariate analysis revealed that sPD-L1 was significantly and independently associated with ACS (OR: 1.004, 95% CI: 1.002-1.006, P&lt;0.001). Conclusions: This is the first clinical study to demonstrate the increased level of sPD-L1 in patients with CAD, and the significant association with ACS.
Abstract 10700: Inverse Relationship Between Cerebral Blood Flow and Systemic to Pulmonary Collateral Flow in Fontans Adjusting for Brain Injury: What Goes up Must Come Down - and Visa Versa
Authors: Mark A Fogel, Elizabeth Donnelly, Ian Crandell, Alex Hanlon, Allie Raevsky, Kevin K Whitehead, Matthew A Harris, Sara Partington, David M Biko, Thomas Flynn, Susan Nicolson, Wehrli Felix, Daniel Licht, Arastoo Vossough
Journal: Circulation (2021)

Introduction: Single ventricle patients develop aortopulmonary collaterals (APC) whose flow (APCF) has been shown, in a cross-sectional study, to be inversely proportional to cerebral blood flow (CBF). Serial longitudinal CBF and APCF data in Fontan patients taking into account brain injury (BI) has never been reported. Decreased CBF may adversely impact neurodevelopmental outcome. Methods: A prospective longitudinal cohort of 27 Fontan patients (age 10 + 1.9 years, 74% male) underwent cardiac and brain MRIs 3-9 months after Fontan and 6.0 + 1.86 years afterwards to measure CBF, APCF and to assess BI (grouped into focal brain injury (FBI), generalized insult (GI) and hemorrhage). CBF was measured using jugular venous flow and APCF was measured by the difference between aortic flow and caval return. A multivariate linear regression model was used to assess the relationship between change in APCF and change in CBF controlling for time since Fontan, sex, and changes in BI. Results: Demographics, flow and BI data are shown in table 1. A strong inverse relationship was found between CBF and APCF when CBF was indexed to aortic flow and APCF was indexed to BSA (R^2 = 0.72, P&lt;0.01). Overall, CBF decreased by 9 + 11% and APCF decreased by 0.73 + 0.67 l/min/m^2 (12% when indexed to aortic flow). CBF and APCF were significantly and inversely related when adjusting for time since Fontan, sex, and change in the visibility of BI on MRI. Each one unit increase in APCF was associated with an 8% decrease in CBF. Change in CBF was smaller for those with longer times since Fontan and was larger for males. Change in CBF was larger for those whose FBI or GI became less visible, but smaller for those whose hemorrhages became less visible. See table 2. Conclusion: CBF and APCF are inversely related across serial imaging, adjusting for time from Fontan, sex and BI. This may adversely impact neurodevelopment. As APCs can be embolized, this may be a modifiable risk factor. A large scale trial is warranted.
Successful Development of an Outpatient Chimeric Antigen Receptor (CAR) T Cell Therapy Program
Authors: Azra Borogovac, Amany R. Keruakous, Michelle Bycko, Jennifer Holter Chakrabarty, Sami Ibrahimi, Mohamad O. Khawandanah, George B. Selby, Carrie Yuen, Sarah A. Schmidt, Taha Al-Juhaishi, Matthew Wieduwilt, Adam S. Asch
Journal: Blood (2021)
NIMG-73. CAPTURING GLIOBLASTOMA HETEROGENEITY USING IMAGING AND DEEP LEARNING: APPLICATION TO MGMT PROMOTER METHYLATION
Authors: Sanjay Saxena, Anahita Fathi Kazerooni, Erik Toorens, Spyridon Bakas, Hamed Akbari, Chiharu Sako, Elizabeth Mamourian, Costas Koumenis, Suyash Mohan, Stephen J Bagley, Robert A Lustig, Donald M O’Rourke, Tapan Ganguly, MacLean Nasrallah, Christos Davatzikos
Journal: Neuro-Oncology (2021)

Abstract PURPOSE Intratumor heterogeneity is frequent in glioblastoma (GB), giving rise to the tumor’s resistance to standard therapies and, ultimately, poorer clinical outcomes. Yet heterogeneity is often not quantified when assessing the genomic or methylomic profile of a tumor, when a single tissue sample is analyzed. This study proposes a novel approach to non-invasively characterize heterogeneity across glioblastoma using deep learning analysis MRI scans, using MGMT promoter methylation (MGMTpm) as a test-case, and validates the imaging-derived heterogeneity maps with MGMTpm heterogeneity measured via multiple tissue samples. METHODS Multi-parametric MRI (mpMRI) scans (T1, T1-Gd, T2, T2-FLAIR) of 181 patients with newly diagnosed glioblastoma, who underwent surgical tumor resection and had MGMT methylation assessment results, were retrospectively collected. We trained a 5-fold cross-validated deep convolutional neural network with six convolutional layers for a discovery cohort of 137 patients by placing overlapping regional patches over the whole tumor on mpMRI scans to capture spatial heterogeneity of MGMTpm status in different regions within the tumor. Our approach effectively hypothesized that despite heterogeneity in the training examples, dominant imaging patterns would be captured by deep learning. Trained model was independently applied to an unseen replication cohort of 44 patients, with multiple tissue specimens chosen from different spatial regions within the tumor, allowing us to compare imaging- and tissue-based MGMTpm estimates. RESULTS Our model yielded AUC of 0.75 (95% CI: 0.65–0.79) for global MGMT status prediction, which reflected the heterogeneity in MGMTpm, but also that a dominant imaging pattern of MGMT methylation seemed to emerge. In methylated patients with multiple tissue samples, a significant Pearson's correlation coefficient of 0.64 (p&amp;lt; 0.05) was found between imaging-based heterogeneity maps and MGMTpm heterogeneity. CONCLUSION A novel method based on mpMRI and deep neural networks yielded imaging-based heterogeneity maps that strongly associated with intratumor molecular heterogeneity in MGMT promoter methylated tumors.
TMOD-19. FROM PATIENT TO PETRI DISH: INCREASING PATIENT-DERIVED GLIOBLASTOMA CULTURE EFFICIENCIES TO 95%
Authors: Cassandra Verheul, Federica Fabro, Ioannis Ntafoulis, Cecile Beerens, Youri Hoogstrate, Trisha Kers, Judith Van den Burg, Stanley Van, Pim French, Miao Chien, Clemens Dirven, Sieger Leenstra, Martine Lamfers*
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The search for effective therapies for gliomas is progressively moving towards patient-specific medicine. In order to test patient-tailored therapies, it is vital to develop protocols for reliable establishment of patient-derived glioma cultures. We present a method for reliable culture establishment, with a 95% success rate in 114 consecutive high-grade samples. METHODS Cell cultures were established from either traditionally-resected tumor tissue or ultrasonic surgical aspirator (CUSA) derived tissue fragments, and expanded in serum-free culture, with selection of astrocytic populations if required. Cultures were started from single cells or small tumor fragments of 0.5-3mm (3D). Whole exome and RNA sequencing were carried out with the Illumina Novaseq and HiSeq platforms. Methylation profiling was performed with the Infinium MethylationEPIC array. Cultures and tumors were compared through analysis of single nucleotide polymorphisms and copy number profiles with the Infinium Global Screening Array. Intra-tumoral heterogeneity in cultures was investigated with single-cell transcriptomic sequencing (SORT-seq). We studied tumor-initiating potential by orthotopic injection of cultures in NOD-SCID mice. RESULTS Cultures started from single cells were established from CUSA material more efficiently (92%) than from traditional resection material (70%). 3D-derived cultures had a higher overall efficiency (95% for CUSA, 85% for traditional resection material). We confirmed high concordance in driver mutations, copy number and methylation profiles between tumors and derived cultures. Transcriptomics analysis, comparing tumors and derived cultures, revealed high consistency in gene expression distribution as demonstrated by correlation analysis (r=0.88). Singe-cell RNA-seq shows increased heterogeneity in CUSA derived-cultures, and decreased heterogeneity with passaging over time. Cultures faithfully produce tumors after orthotopic injection in NOD-SCID mice. CONCLUSION We present a highly successful method for the establishment of glioma cultures from patient material, with CUSA-derived cultures revealing greater heterogeneity. Cultures faithfully represent important molecular characteristics of parental tumors and can be used to test potential therapies in vitro.
Abstract 14470: Novel Autophagy Mechanisms of NP-6A4 Protection in Heart Disease Induced by Untreated Obesity
Authors: Asma Boukhalfa, Anthony Belenchia, Vincent De Marco, Pei Liu, Brian Mooney, Alexander Mehm, Yinian Tang, Lauren Ling, madhavi gavini, Howard H Chen, Lakshmi Pulakat
Journal: Circulation (2021)

Introduction &amp; Hypothesis: Untreated obesity induces insulin resistance and heart disease affecting 42% of the US population. Autophagy, a conserved homeostatic process for cellular quality control, plays a critical role in maintaining health. Heart tissues of obese humans and rodent models show impaired autophagy. Drugs that can regulate autophagy are thus of high clinical significance. We reported recently that NP-6A4, a new peptide agonist of the cardiovascular protective angiotensin receptor AT2R, mitigated obesity-induced cardiac dysfunction and damage in rats with untreated obesity and pre-diabetes. We hypothesized that activation of autophagy by NP-6A4 is involved in NP-6A4-AT2R-induced cardioprotection in untreated obesity. Methods &amp; Results: 7-week old female ZDF rats fed high fat diet (D12468, Research Diet) for 6 weeks were randomized to receive either NP-6A4 (10mg/kg/day), NP6A4+AT2R antagonist PD123319 (PD, 5mg/kg/day) delivered subcutaneously (N=6/group), or vehicle (N=5) for 4 weeks. Echocardiography showed that NP-6A4 reduced abnormal E/A ratio from 2.1 to 1.45 (P&lt;0.006), and isovolumic contraction (P&lt;0.004) and relaxation times (P&lt;0.02), and increased myocardial radial strain (P&lt;0.019) and radial strain rate (P&lt;0.033). PD reversed these effects. Immunohistochemistry (IHC) and Western blot analysis revealed a significant 5.9-fold increase (p&lt;0.0006) in LC3 puncta (Fig. A-B) and 2.2-fold increase (p&lt;0.0008) in lipidated autophagy marker LC3-II (Fig. C) compared to vehicle controls. The autophagy activation by NP-6A4 was not seen with the co-administration of PD (Fig. A-C). Cardiac proteome analysis showed that Sec16a, an important partner of autophagy initiators ULK1/2 is increased in ZDF rat heart by NP-6A4 (2.75 fold; P&lt;0.020), but PD suppressed this effect. Conclusions: We identified NP-6A4’s dual targeting of AT2R and novel autophagy regulation to mitigate cardiac dysfunction induced by untreated obesity in female rats