tbuckley/cabot-search huggingface dataset:
TAMI-64. IMMUNE ENVIRONMENT SHAPES GLIOBLASTOMA HETEROGENEITY IN TIME AND SPACE
Authors: Paulina Will, Jan Kückelhaus, Jasim Kada Benotmane, Kevin Joseph, Jürgen Beck, Oliver Schnell, Vidyha Ravi, Dieter Henrik Heiland
Journal: Neuro-Oncology (2021)

Abstract Glioblastomas are embedded into an immunosuppressive microenvironment resulting in limited success of immunotherapies. Although, we and others observed defined myeloid-tumor crosslinks reducing T cell homing and activation, the spatial context of these interactions remained unexplored. Here, we provide evidence, that local T cell infiltration results in a defined activation of myeloid cells causing transcriptional reprogramming of tumor cells reminiscent of reactive transformation in mature astrocytes. Through integration of spatially resolved transcriptomics and imaging mass cytometry (n=18, 39 protein glioma panel) we mapped defined transcriptional responses in areas of high or low T cell infiltration respectively. Functional analysis revealed that areas of large T cell infiltration are enriched for glial (CHI3L1, GFAP and VIM) and inflammatory genes (HLA-DRA, C3, CCL4, CCL3). We found that marker genes of common reactive states in mature astrocytes significantly overlap with the reactive immune program of glioblastoma cells (f-score 0.76, p=2.2e-10). Increased numbers of CD163+ cells were found in surrounding areas of T cell infiltration and spatially linked to defined immunosuppressive release of IL10, recently reported as a major driver of T cell exhaustion. To support our findings, we injected a primary glioblastoma cell line into cortex slices of three different human and rodent donors. After 7 days of tumor growth, we performed scRNA-sequencing of FACS-sorted tumor cells and baseline cell culture cells. Compared to baseline, we found cells of all reported transcriptional states, confirming the dynamic adaptation of cells within a neural environment. In elderly donors, a significant accumulation of reactive immune programs (ANOVA p&amp;lt; 0.001) was observed. Immunostainings confirmed an increased myeloid cell activation in these donors. Our data suggest that inflammatory stimuli in the glioblastoma microenvironment cause transcriptional reprogramming in glioblastoma similar to inflammatory transformation of reactive astrocytes. The spatial exclusivity of these programs highlights the value of a spatial perspective on heterogeneity.
Abstract 12181: Targeted Intra-Coronary Delivery versus Intra-Myocardial Injection of Therapeutics for Myocardial Recovery: A Nanoparticle Image Guided Porcine Study
Authors: Andrew M Vekstein, David C Wendell, Dawn E Bowles, Sophia DeLuca, Ruorong Yan, Muath Bishawi, Garth Devlin, Aravind Asokan, Kenneth D Poss, Nenad Bursac, Adam R Williams
Journal: Circulation (2021)

Introduction: The optimal cardiac delivery route for stem cell and gene therapeutics is poorly understood. Direct intramyocardial (IM) injection has been proposed as the gold standard, however, it is invasive and not studied in detail against targeted intra-coronary (IC) delivery techniques. We sought to compare effectiveness of IM and targeted IC methods using cardiac magnetic resonance imaging (CMR) of nanoparticles in a porcine model. Hypothesis: IM provides the highest retention of delivered therapeutic, while targeted IC delivery yields high-volume retention in the perfused coronary territory. Methods: In Yorkshire swine (n=10), 5ml of ferumoxytol iron oxide (IO) nanoparticles, similar in size to therapeutic viral vectors, were injected: 1) IM via thoracotomy (n=3), 2) catheter based IC balloon-occlusion (BO) with distal infusion of the LAD (n=4), 3) IC with perforated balloon side wall (SW) infusion in the LAD (n=2), or 4) IC non-selective left main (LM) (n=1). Hearts were harvested and imaged with CMR using T1 and 3D inversion-recovery sequences. Retention of nanoparticles was quantified by percent of myocardium occupied. Results: IM delivery yielded the highest retention (16.3±5.5% of myocardial volume, p=0.04). Of the IC approaches, BO had the highest retention (8.7±2.2%, p=0.13 vs IM) compared to SW (5.5±4.9%) and LM (0%). On 3D CMR, BO yielded consistent uptake in the distal LAD territory, including the anterior wall and septum. IM delivery was limited to the anterior wall with no nanoparticles in the septum. Troponin increased 15,600±4,910 with IM vs.184±262 with IC (p=0.14). Conclusions: Direct IM injection offers the highest retention of delivered therapeutics to the heart. IC balloon occlusion-distal infusion has highest retention among IC techniques and provides an effective approach to direct therapeutics to the vascular bed most impacted by an infarct.
Abstract 9566: Quantification of Valve Regurgitation in the Pediatric Population Using 3-Dimensional Echocardiography: Feasibility and Comparison With Cardiac Magnetic Resonance Imaging
Authors: Joseph D Kuebler, Melinda H Shea, Minmin Lu, Lynn A Sleeper, David M Harrild, Ashwin Prakash, Gerald R Marx
Journal: Circulation (2021)

Introduction: Valvar regurgitation in pediatric patients is commonly assessed by cardiac magnetic resonance (CMR). This modality is associated with increased cost and need for anesthesia in young patients when compared to echocardiography. 3-dimensional echocardiography (3DE) can measure ventricular volumes and calculate the regurgitation fraction (RF) by comparison of stroke volumes - similar to CMR. Given the potential advantages of 3DE in children, this study sought to compare the quantification of single valvar regurgitation using 3DE versus CMR as the gold standard. Methods: Pediatric patients ≤18 years of age were included in the study. Patients were excluded if they had more than mild regurgitation of an additional valve, significant shunt, or suboptimal imaging windows. Full volume data sets were obtained sub-costally using a Philips IE33 or EPIQ CVx machine (X5 or X7 ultrasound probe). 3DE volumes were analyzed using 4D Cardioview (Tomtec Imaging Systems) and compared with ventricular volumes and RF obtained by CMR. Inter- and intra-observer reliability were assessed for 3DE ventricular volumes and RF. Results: 34 patients had volumes obtained by 3DE and CMR with two patients having pairs of studies performed on different dates. The median age was 8.7 (IQR; 3.9-12.3) years. 12 studies (33%) were obtained under sedation. Primary valve involvement was: mitral-12 (33%), tricuspid-9 (25%), pulmonary-1 (3%), and aortic-14 (39%). Agreement between 3DE and CMR ventricular volumes by intraclass correlation coefficient (ICC) was excellent (ICC&gt;0.90). Agreement for the regurgitant fraction was good (ICC 0.80 (95% CI; 0.68, 0.88)). Ventricular volume ratios obtained by MRI and 3DE were strongly correlated; Spearman r = 0.92 (95% CI; 0.85-0.96). Inter-observer reliability was excellent for ventricular volumes and moderate for RF (ICC 0.63 (95% CI; 0.23, 0.85)). Intra-observer reliability was excellent for ventricular volumes and RF (ICC≥0.97). Conclusions: Assessment of single valvar regurgitation using 3DE compares favorably with CMR in pediatric patients. The shorter time for image acquisition and lower cost will allow for standard application of 3DE to measure single valve regurgitation in this population, particularly on a serial basis.
Abstract P397: <i>MTCH2</i> As A Modifier Of Cardiomyopathy
Authors: Julie A Fischer, Megan Puckelwartz, Matthew Wolf, Mattia Quattrocelli, Lorenzo Pesce, Rosemary Bauer, Samuel Kearns, Elizabeth M McNally
Journal: Circulation Research (2021)

Background: Cardiomyopathy is a highly heritable disorder that carries a significant risk for heart failure and arrhythmias. Most inherited cardiomyopathies are characterized by variable penetrance and expressivity, which in part arises from additional genetic variation, known as genetic modifiers. Methods and Results: Genomic profiling of human cardiomyopathy cases identified enriched genetic variation in the gene MTCH2. Specifically, a truncating variant was found to be overrepresented in patients with cardiomyopathy compared to controls. MTCH2 encodes a mitochondrial carrier protein that has a role in regulating oxidative phosphorylation. To investigate fundamental mechanisms by which MTCH2 contributes to cardiac and metabolic phenotypes, we generated a knockdown model of the Drosophila MTCH2 ortholog, Mtch. We found that cardiac-specific Mtch reduction in flies produced heart tube dilation and reduced function as well as a shortened life span, documenting a clear role Mtch in the myocardium. Metabolomic profiling demonstrated cardiac deficiency of Mtch lowered the flux of glucose-derived metabolites to the citric acid cycle associated with reduced downstream oxygen consumption and ATP synthesis, causing an energy deficit. We generated a deletion of MTCH2 using gene editing in HEK293 cells. Similar to the fly model, these cells demonstrated reduced oxygen consumption in the presence of glucose, but not fatty acids, and had a higher level of inhibitory phosphorylation of pyruvate dehydrogenase, a critical regulator of glucose metabolism. These data suggest MTCH2 influences the efficiency of glucose oxidation and substrate usage, an important mode of cardiac energy generation, especially in the setting of heart failure. Conclusions: We identified MTCH2 as a modifier of the cardiomyopathy phenotype in humans. Reduction of MTCH2 resulted in impaired cardiac function with reduced oxygen consumption and increased glycolysis in a substrate dependent manner. Since failed hearts are more dependent on glycolysis, these data support that reduction of MTCH2 promotes heart failure and provides a mechanism by which MTCH2 acts as a deleterious genetic modifier in heart failure.
EXTH-47. SAFETY AND EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION ON GLIOBLASTOMA MEASURED IN VITRO
Authors: Christen O'Neal, Sydney Scott, Tressie Stephens, Patrick McKernan, Arpan Chakraborty, Anish Babu, Alexander Evans, Chad Glenn, James Battiste
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Although gross total resection (GTR) with chemoradiation is the standard of care for treating glioblastoma (GBM), tumor infiltration and treatment sequelae can impair activity of eloquent regions. Transcranial magnetic stimulation (TMS) has been explored as an adjunct therapy to rehabilitation for post-stroke motor deficits. TMS could be effective for postoperative rehabilitation in GBM, but its effect on GBM cells has not been evaluated. While TMS utilizes magnetic fields to induce electrical currents at low frequencies to cause neuronal excitation or inhibition, tumor-treating fields (TTF) utilize electrical currents with intermediate frequency to exert anti-mitotic effects, demonstrating promise as an adjunctive therapy in recurrent GBM. Although similarities exist between electrical and magnetic fields, the effects of magnetically induced electrical currents at low frequencies via TMS must be studied systematically in vitro on GBM cell lines. METHODS We studied the effect of theta burst stimulation (TBS), a form of patterned TMS, on in vitro G55 cell viability using colony forming assays. We compared TMS-treated cells to controls using a combination of parameters: continuous versus intermittent TBS (cTBS and iTBS), 300 versus 600 pulses, stimulation intensity of 32% versus 60%, and no pre-TMS chemotherapy versus 100 nM or 100 µM temozolomide (TMZ). Viability measurements between controls and TMS were analyzed using analysis of variance (ANOVA). Independent t-tests were used to analyze effects of stimulation parameters on viability percent difference within each TMZ condition. RESULTS There was no statistically significant increase in viability between control and TMS conditions for any of the stimulation parameters (+/- TMZ) while some showed decreased viability of GBM cells. CONCLUSIONS TMS did not significantly increase GBM viability compared to controls. Future studies include validation in other cell lines and characterization of the effects of stimulation parameters in conjunction with TMZ and dexamethasone, (often administered concurrently with GBM treatment).
Abstract 10280: The Association of Obesity Level and In-Hospital Survival of Patients with Covid-19 Who Received Corticosteroids
Authors: Matsuo So, Mai Takahashi, Natalia Egorova, Toshiki Kuno
Journal: Circulation (2021)

Introduction: Obesity is one of the most frequent comorbidities among COVID-19 patients. Although previous studies have shown higher body mass index (BMI) is associated with higher mortality, steroids as the current standard treatment for moderate to severe COVID-19 infection were not applied in most patients in these studies. Hypothesis: We hypothesized that patients with higher BMI still have higher mortality even on steroids. Methods: We conducted a retrospective study of 4,587 hospitalized patients with COVID-19 who received corticosteroids between March 1 st , 2020, and March 30 th , 2021. We divided patients into 6 groups by BMI[MOU1] (less 18.5, 18.5-25, 25-30, 30-35, 35-40, 40 or greater, kg/m 2 ) and investigated in-hospital mortality as the primary outcome, in-hospital mortality among severe COVID-19 patients which was defined as requiring intensive care unit or endotracheal intubation as a subgroup analysis, and acute kidney injury (AKI) incidence rate as the secondary outcome. Results: Patients with higher BMI were younger and more likely to have a history of asthma, obstructive sleep apnea, diabetes, and less likely to have malignancies. The smooth spline curve showed J curve association of BMI with risk adjusted in-hospital mortality with flexion point at BMI between 25 and 30 kg/m 2 (Figure 1). Compared to overweight (25≤BMI&lt;30 kg/m 2 ) patients, class III obesity (BMI&gt;40 kg/m 2 ) was associated with higher risk adjusted in-hospital mortality overall (Table 1) as well as among patients with severe COVID-19 (OR [95% CI]: 3.21 [1.86-5.66], P&lt;0.001). Class III obesity was also associated with a higher risk adjusted incidence of AKI (OR [95% CI]: 1.52 [1.06-2.18], P=0.024) compared to overweight patients. Conclusions: Class III obesity was associated with higher in-hospital mortality and AKI incidence rate in COVID-19 patients with steroids treatment.
Abstract 9318: Cardiac Computed Tomography versus Transesophageal Echography for the Detection of Left Atrial Appendage Thrombus: A Systemic Review and Meta-Analysis
Authors: Shandong Yu, Hongwei Li
Journal: Circulation (2021)

Introduction: Transesophageal echocardiogram (TEE) has been considered the gold standard for left atrial appendage (LAA) thrombus detection. Nevertheless, TEE is a semi-invasive and time-consuming procedure that may sometimes induce discomfort and cause complications. Cardiac computed tomography (CCT) has been studied extensively for LAA thrombus detection. Hypothesis: We performed this systemic review and meta-analysis to assess the diagnostic accuracy of CCT for LAA thrombus detection compared with TEE. Methods: A systemic search was conducted in the PubMed, Embase and Cochrane Library databases. Sensitivity, specificity and posterior probability were calculated to assess the diagnostic accuracy of CCT. Results: A total of 27 studies involving 6852 were included in our study. The summary sensitivity was 0.98 (95% CI, 0.91-1.00), and the specificity was 0.96 (95% CI, 0.92-0.98). Based on the overall LAA thrombus incidence, the positive posterior probability was 53.21%, and the negative posterior probability was 0.08%. In the subgroup analysis of the early and delayed imaging groups, the delayed imaging method significantly improved the specificity and positive posterior probability. The summary sensitivity of early imaging studies was 0.95 (95% CI, 0.79-0.99), and the specificity was 0.89 (0.85-0.92). The positive posterior probability was 19.11%, and the negative posterior probability was 0.16%. The summary sensitivity of delayed imaging studies was 0.98 (95% CI, 0.92-1.00), and the specificity was 1.00 (0.98-1.00). The positive posterior probability was 95.76%, and the negative posterior probability was 0.12%. Conclusions: Compared with TEE, CCT with a delayed imaging method has good diagnostic accuracy for LAA thrombus detection.
Abstract 13960: Socioeconomic and Environmental Exposures (Socio-Enviromics) and Cardiometabolic Health in the United States
Authors: Sadeer Al-Kindi, Graham Bevan, Anant Madabhushi, Phillip Levy, Khurram Nasir, Thomas Munzel, Robert D Brook, Sanjay Rajagopalan
Journal: Circulation (2021)

Introduction: Environmental exposures and socioeconomic status may have complex interactions at the neighborhood level with respect to contributionto cardiovascular disease. We sought to understand the association between integreated social/environmentalexposures (socio-enviromics) with geospatial variation in various chronic cardiometabolic and pulmonary conditions in the United States. Methods: We mapped 27 census tract (CT)-level multi-source environmental exposure and socioeconomic variables throughout more &gt;70,000 census tracts in the US. We trained a regression-based machine learning model using 80% training and tested it on 20% hold-out test to predict CT-level estimated prevalence of various risk factors and chronic diseases. We additionally tested the association between the predicted prevalence of coronary artery disease (socio-enviromic score) with major adverse cardiovascular events (MACE) in a prospective cohort of 45,188 individuals who underwent coronary artery calcium (CAC) score testing using cox regression model. Results: Enviromics/SocioEnviromics explained significant proportion of variation in prevalence of health conditions (figure). In the CAC cohort, socio-enviromic score was associated with MACE independently of age, sex, race and CAC (HR 1.12 [1.08-1.17], P&lt;0.001). The association between socioenviromic score and MACE was stronger among individuals with lower CAC (socioenviromic score * CAC P interaction =0.01). Conclusions: A significant proportion of the census-tract level prevalence of cardiometabolic conditions can be explained by geographic variation in socio-enviromics, and an integrated socio-enviromic score is associated with MACE at the individual level, independently of CAC. The impact of integrated socio-enviromics in individual cardiovascular risk prediction should be studied in prospective cohorts.
QOLP-30. LONG-TERM UNMET SUPPORTIVE CARE NEEDS OF TYA CHILDHOOD BRAIN TUMOUR SURVIVORS AND THEIR CAREGIVERS: A CROSS-SECTIONAL SURVEY
Authors: Emma Nicklin, Galina Velikova, Adam Glaser, Michelle Kwok-WIlliam, Miguel Debono, Naseem Sarwar, Florien Boele
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The supportive care needs of long-term childhood brain tumour survivors, now teenagers and young adults (TYAs), and their caregivers are largely unknown. TYAs are a unique patient cohort with specific challenges and vulnerabilities differing from children or older adults. We aimed to describe their supportive care needs and explore associations between needs and quality of life (QoL).This is the first study to collect quantitative data about needs in this survivorship group. METHODS Participants were recruited from long-term follow-up clinics (in three National Health Service Trusts in England) and online. Participants included childhood brain tumour survivors, ≥ 5 years from diagnosis, currently aged 13-30, and their primary caregivers. Survivors completed the Supportive Care Needs Survey (SCNS) Short-Form and Paediatric Functional Assessment of Cancer Therapy – Brain (Peds-FACT-Br). While caregivers completed the SCNS-Partners and Caregivers (SCNS-P&amp;C) and the Caregiver Quality of Life Index–Cancer (CQOLC). RESULTS In total, 112 individuals (69 survivors/43 caregivers) participated. Survivors reported on average 9.4 (±8.5) unmet needs. Needs were greatest in the psychological domain, with anxiety (60.3%), uncertainty about the future (50.7%) and feeling down and depressed (48.5%) most commonly reported. Caregivers reported on average 12.4 (±12.3) unmet needs. Again, the greatest number of unmet needs were observed in the psychological domain. Many caregivers also reported information needs around financial support/government benefits (42.9%) and possible survivor fertility problems (42.9%). Multivariable linear regression analysis showed that female survivors, unemployed survivors, survivors further away from diagnosis, and single caregivers were more likely to report unmet needs. More unmet needs were significantly associated with poorer QoL in survivors and caregivers. CONCLUSION This research provides leads to improving supportive care and long-term follow-up services. Psychological support appears to be the biggest gap in care. Understanding unmet needs and recognising what services are required is critical to improving quality of long-term survival.
CNTM-06. Individual Cerebrocerebellar Functional Network Analysis for Decoding the Symptomatological Dynamics of Posterior Fossa Syndrome
Authors: Ko-Ting Chen, Sheng-Yao Huang
Journal: Neuro-Oncology (2021)

Abstract Posterior fossa syndrome (PFS) consists of three types of symptom (motoric, linguistic, and neurobehavioral) in patients with posterior fossa pathologies. The evolutional mechanism of this high cognitive syndromic complex from cerebellar origin remains unconfirmed. Previous studies analyzing PFS patients mostly focused on the association between structural abnormalities that occur during PFS, of which proximal efferent cerebellar pathway (pECP) injury appears to be the most common pathogenesis. However, structural imaging may not be sensitive enough to determine the dynamic course of PFS, since the symptomatology is primarily an output of cerebral operation. On the other hand, a network neuroscience approach using a mathematical model to extract information from functional imaging to generate interregional connectivity provides abundant evidence that the cerebellum is influential in modulating cerebral functions. This study applied a network approach to children with PFS. Scaling of each symptom domain was used to quantify the dynamics of the syndrome. An individual cerebrocerebellar functional network analysis was then performed to determine the network dynamics during PFS. Cross-validation of clinical neurophysiology and functional neuroscience suggested the critical role of the pECP within PFS from the network analysis. The employed approach was therefore useful in determining the complex clinical symptoms using individual functional network analysis, which bridges the gap between structural neuroimaging and clinical neurophysiology.