tbuckley/cabot-search huggingface dataset:
Abstract 14381: High Coronary Artery Calcium Score Predicts Earlier and More Frequent Need for Cardiac Revascularization - A Large Scale, Single Center Study
Authors: kevin coy, Zoltan Varga, Beatrice Rynders, Alexander Sjovold, Veronica Stys, Mark Petrasko, Phillip Petrasko, Melissa Pham, patryk stys, Komaldeep Singh, Aditya singh, Muhammad Hamza Saad Shaukat, Catherine Hajek, Murat Sincan, Marian S Petrasko, Adam Stys, Tom Stys
Journal: Circulation (2021)

Introduction: Coronary artery calcium score (CAC) predicts the risk of cardiac events with need of revascularization. CAC scores indicate plaque burden and are classified as low (&lt;100), moderate (100-399) or high (≥400). Hypothesis: High CAC score predicts earlier and more frequent need for cardiac revascularization (CABG or PCI) compared to low CAC score. Methods: A total of 60,719 subjects were screened for CAC score from which 1,861 underwent subsequent coronary revascularization if clinically indicated. Patients with moderately elevated CAC scores were excluded from the analysis. The incidence and timing of revascularization was compared between the low and high CAC score groups using two sample Z test. Wilcoxon rank sum test was used to calculate medians. Results: The analysis included 47 937 patients in the low CAC score group (mean age of 53.6 ± 9.9 with 59.5% female) and 5415 in the high CAC score group (mean age of 64.8 ± 8.4 with 28.2% female). As shown in Table 1, the incidence of cardiac revascularization was significantly higher in the high CAC score group (p &lt; .0001). Average time to intervention was significantly shorter in the high CAC score group (p &lt; .0001). Conclusions: Significantly higher rates of cardiac revascularization were observed in patients with high CAC score. In these individuals, the average time to revascularization was found to be lower than in the low CAC group. Low CAC score individuals had nearly double the time to an event, which is a finding with potentially high clinical significance.
Abstract 10841: Clinical Significance of Left Atrial Function Estimated by Two Dimensional Speckle Tracking Echocardiography for Diagnosis of Concomitant Transthyretin Amyloid Cardiomyopathy in Patients with Aortic Stenosis
Authors: Fumi Oike, Hiroki Usuku, Eiichiro Yamamoto, Seiji Takashio, Masanobu Ishii, Daisuke Sueta, Shinsuke Hanatani, Satoshi Araki, Hirofumi Soejima, Kenichi Matsushita, Kenichi Tsujita
Journal: Circulation (2021)

Background: Aortic stenosis (AS) and transthyretin amyloid cardiomyopathy (ATTR-CM) are common in the elderly. We evaluated the usefulness of two-dimensional (2D) speckle strain imaging to diagnose concomitant ATTR-CM in patients with AS. Methods and Results: We analyzed 72 consecutive patients with moderate to severe AS who underwent 99m Tc-pyrophosphate (PYP) scintigraphy, a useful modality for diagnosis of ATTR-CM, at Kumamoto University Hospital from January 2012 to September 2020. There were no significant differences in the baseline clinical characteristics or conventional echocardiographic findings between the 99m Tc-PYP scintigraphy-positive and -negative groups. In 2D speckle strain imaging of the left ventricle, the relative apical longitudinal strain (LS) index [apical LS/ (basal LS + mid LS)] was significantly higher in the 99m Tc-PYP scintigraphy-positive than -negative group (p&lt;0.05). In 2D speckle strain imaging of the left atrium (LA), the peak longitudinal strain rate (LSR) and the late LSR were significantly lower in the 99m Tc-PYP scintigraphy-positive than -negative group (peak LSR:0.36±0.14 vs. 0.55±0.20, p&lt;0.05 and late LSR:0.26±0.25 vs. 0.52±0.29, p&lt;0.05, respectively). In the receiver-operating-characteristic analysis, the peak LSR in the LA was the most effective echocardiographic parameter for 99m Tc-PYP scintigraphy positivity (area-under-the-curve, 0.79). Multivariable logistic analysis using two forced inclusion models identified the peak LSR in the LA was more significant factor of 99m Tc-PYP scintigraphy positivity in patients with AS. Conclusion: The peak LSR in the LA may be a useful predictor of the presence of ATTR-CM in patients with AS.
RTID-01. PHASE III MULTICENTER RCT OF POST-SURGICAL STEREOTACTIC RADIOTHERAPY VERSUS SURGICALLY TARGETED RADIATION THERAPY FOR THE TREATMENT OF LARGE NEWLY DIAGNOSED BRAIN METASTASES – TRIAL IN PROGRESS
Authors: Jeffrey Weinberg, Thomas Beckham, Mary Frances McAleer, Jason Michael Johnson, Ying Yuan, Heather Lin, Rajat Kudchadker, Theodore Schwartz, Jonathan Knisely, Erin Dunbar, David McCracken, Jeffrey Wefel
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Resection (R) followed by single- or multi-fraction stereotactic radiosurgery (SRT) of brain metastases (BMs) lowers resection bed recurrence compared to R alone. Nevertheless, for larger BMs, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiotherapy. STaRT allows rapid, intense localized radiation dose delivery directly to the tumor bed with predictable dosimetry immediately at the time of R, which may confer reduced risk for radiation necrosis compared to other therapies. It is hypothesized that R+ STaRT will increase surgical bed recurrence-free survival (SB-RFS), while reducing impact on functional and neurocognitive status compared to R+SRT. METHODS Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” BMs (≥ 2.5–5cm), and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo R+SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 14 sites. Enrollment opened 03/31/2021. First subject was enrolled 04/07/2021. Primary endpoint is SB-RFS. Secondary endpoints include overall survival, quality of life, neurocognition, functional status, imaging findings and adverse events. Follow-up will be through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures captured will elucidate the potential risks and benefits of these two RT delivery methods in the setting of newly diagnosed BMs. We will present trial accrual progress, available data, experience and lessons learned.
Abstract 12297: Myocardial Bridging Increases the Risk of Preoperative Atrial Fibrillation in Adult Patients with Obstructive Hypertrophic Cardiomyopathy
Authors: Changrong Nie, Changsheng Wang, Yunhu Song, Minghu Xiao, WANG Shuiyun
Journal: Circulation (2021)

Background: Myocardial bridging (MB) was associated with various arrhythmia forms like supraventricular tachycardia, ventricular tachycardia, atrioventricular conduction block, and sudden cardiac death. However, the relationship between MB and preoperative atrial fibrillation (AF) remains unknown. Hypothesis: The presence of MB increases the risk of preoperation AF in adult patients with obstructive hypertrophic cardiomyopathy (OHCM). Method: We recruited 968 consecutive patients with OHCM who underwent surgical myectomy at Fuwai Hospital in Beijing, China, from January 2015 to December 2019. Patients were divided into two groups based on invasive coronary angiography: patients with MB group (N=144) and patients without MB group (N=824). Result: Patients with MB were much younger (43.6 vs. 48.8 years, p &lt; 0.001), more likely to have palpitation (37.4% vs. 25.5%, p = 0.003), had a lower body mass index (24.8 vs. 25.7 kg/m2, p = 0.009), a lower incidence of hypertension (14.6% vs. 27.9% p = 0.001), a higher prevalence of AF (26.4% vs. 11.5%, p &lt;0.001). After adjusting for age, sex, left atrial diameter, and LVOT gradient, multivariate logistic regression analysis revealed that the presence of MB was independently associated with AF (Odds ratio [OR] 3.73; 95% Confidential interval [CI] 2.32-5.98, p &lt; 0.001). Furthermore, we conducted a LASSO logistic regression to select variables associated with AF from patients with MB subgroup, and five non-zero variables were included in the multivariate logistic regression model. The results indicated that compared to patients with MB on the middle left anterior descending coronary (LAD), those with MB on the proximal LAD had a higher likelihood to develop AF (OR 4.22; 95% CI 1.40-12.68, p = 0.01). Moreover, MB compression (OR 1.04; 95% CI 1.04-1.08, p = 0.013) and MB length (OR 1.06; 95% CI 1.004-1.11, p = 0.034) were independently associated with a higher prevalence of AF after adjusting for age and left atrial diameter. Conclusion: The presence of MB and its location, length, and compression degree were independently associated with an increased risk of preoperative AF in adult HOCM patients, which suggested that whether MB needed surgical treatment during septal myectomy should be considered.
Abstract MP233: Investigating Genotoxic-induced Innate Immune Pathways Leading To Heart Failure With Preserved Ejection Fraction For Developing Effective Treatments
Authors: Mohammad H Al-Khalaf, David Smyth, Gauri Akolkar, Justin Williams, Liyong Zhang, Kenneth Yip, Ren-Ke Li, Fei-Fei Liu, Peter P Liu
Journal: Circulation Research (2021)

Background: A hallmark of heart failure pathologies is excessive and cumulative DNA damage, leading to an increased and accelerated cardiac cellular senescence. We aimed to investigate the role of DNA breaks in inducing inflammation leading to adverse remodeling, premature senescence, and cardiac dysfunction leading to onset of Heart Failure with preserved Ejection Fraction (HFpEF), a specific type of disease prevalent in the aging population. Results: We use heart-focused ionizing radiation, a novel in vivo technique to induce aging related DNA damage and onset of diastolic dysfunction and HFpEF (n= 4-5 per group &amp; per species; animals used: Rattus norvegicus and Mus musculus). We performed functional analysis, histological tissue assessment and molecular investigations to evaluate and validate this novel animal model technique. DNA damage response is upregulated in aging-related Heart Failure, and here demonstrated in our novel heart-focused radiation technique. Using in vitro ionizing radiation exposure alters cardiomyocyte morphology and activates inflammation, leading to upregulation of fibrosis and senescence markers. Finally using experimental inhibitor compounds targeting the cGAS-STING axis of innate immunity, we show effective attenuation of this relevant pathway, leading to decreased systemic inflammation, cardiomyocyte remodeling, and senescence associated with DNA damage injury. Conclusions: We present a novel technique to induce genotoxic outcomes and inflammation of the heart, leading to HFpEF pathology. We elucidate novel connections from the onset and accumulation of unresolved DNA damage, to activation of specialized innate immune cellular responses, and ultimately upregulation of cardiac tissue specific inflammation, fibrosis and senescence. Finally we demonstrate that antagonizing the cGAS-STING pathway could allow a precision medicine approach to treating genotoxic and inflammatory HFpEF.
Exposure to green-blue spaces and mental health: a retrospective e-cohort study in Wales
Authors: Daniel A Thompson, Richard Fry, Alan Watkins, Amy Mizen, Ashley Akbari, Joanne Garrett, Rebecca Geary, Rebecca Lovell, Ronan A Lyons, Mark Nieuwenhuijsen, Francis Rowney, Gareth Stratton, Benedict Wheeler, Mathew White, James White, Sue Williams, Sarah E Rodgers
Journal: The Lancet (2021)
NIMG-50. DEUTERIUM METABOLIC IMAGING OF THE ALTERNATIVE LENGTHENING OF TELOMERES PATHWAY REPORTS ON TUMOR BURDEN AND PSEUDOPROGRESSION IN LOW-GRADE GLIOMAS
Authors: Céline Taglang, Georgios Batsios, Joydeep Mukherjee, Meryssa Tran, Anne Marie Gillespie, Donghyun Hong, Sabrina Ronen, Hema Artee Luchman, Russell Pieper, Pavithra Viswanath
Journal: Neuro-Oncology (2021)

Abstract Glioma patient management relies heavily on magnetic resonance imaging (MRI). However, MRI is often inadequate for assessment of tumor burden and pseudoprogression. Non-invasive methods that report on molecular pathways such as telomere maintenance that drive tumor proliferation are needed. Among brain tumors, low-grade astrocytomas (LGAs) use the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. The goal of this study was to identify ALT-linked metabolic alterations that can be exploited for non-invasive magnetic resonance spectroscopy (MRS)-based imaging of LGAs. We examined the patient-derived BT257 model and compared neurospheres that are ALT-dependent (BT257 ALT+) with those in which the ALT pathway has been silenced (BT257 ALT-). Our studies suggest that expression and activity of the rate-limiting glycolytic enzyme phosphofructokinase-1 are significantly higher in BT257 ALT+ neurospheres relative to ALT-, an effect that is associated with elevated glucose flux to lactate. Studies indicate that poly(ADP-ribose) polymerase inhibitors such as niraparib selectively induce telomeric fusion and cell death in ALT-dependent cells. We find that the telomeric fusion-mediated cytotoxicity of niraparib is associated with significantly reduced glycolytic flux in BT257 ALT+ neurospheres. We then examined whether 2H-MRS using [6,6’-2H]-glucose, which is a clinically translatable method of imaging glycolytic flux, can be used to monitor the ALT pathway in vivo. [6,6’-2H]-glucose flux to lactate is elevated in tumor relative to normal brain in mice bearing orthotopic BT257 tumors. Importantly, following treatment of BT257 tumor-bearing mice with niraparib, lactate production from [6,6’-2H]-glucose is significantly reduced at early timepoints when alterations in tumor volume cannot be observed by MRI, pointing to the ability of [6,6’-2H]-glucose to report on pseudoprogression in vivo. Collectively, our studies mechanistically link the ALT pathway with elevated glycolytic flux via phosphofructokinase-1 and identify deuterium metabolic imaging as a novel, non-invasive method of imaging tumor burden and treatment response in LGAs in vivo.
EPCO-10. INTRATUMORAL HETEROGENEITY OF ENVIRONMENT-INDUCED EXPRESSION PROGRAMS IN GLIOMA PATIENTS AND DERIVED MODEL SYSTEMS
Authors: Nicholas Bayley, Christopher Tse, Henan Zhu, Lisa Ta, Lynn Baufeld, Laura Gosa, Weihong Yan, Robert Prins, William Yong, Timothy Cloughesy, Linda Liau, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2021)

Abstract Bulk tumor and single-cell RNA sequencing have revealed the remarkable molecular heterogeneity and plasticity of gliomas. This has led to the creation of tumor subtypes and cellular states describing inter- and intra-tumoral heterogeneity, respectively. While there has been great interest in creating and revising new classifications, the biological reasons for this degree of heterogeneity and the selective pressures driving it remain to be fully described. The brain tumor microenvironment (TME) is a complex, regionally heterogeneous ecosystem of communicating normal and malignant cell types and scavenge-able nutrients and metabolites. We hypothesized that distinct cellular interactions and metabolic flux in the TME may drive the inter- and intra-tumoral heterogeneity of gliomas. To identify tumorigenic programs impacted by environmental context we performed bulk RNA sequencing of over 35 triplets of patient glioma samples and their matched derivative models established in direct orthotopic mouse xenografts (DPDOX) and conventional gliomasphere cultures (GS). This analysis revealed environment-specific programs including in vivo immune and neuroglial signaling, in vitro lipid metabolism, and cell migration altered in model systems. These environmental programs are enriched in specific tumor subtypes and neuroglial signaling programs lost in vitro are dynamically upregulated upon re-transplantation in vivo. To further investigate associations between tumor cellular state and environment-driven programs we performed single-cell RNA sequencing of 3 patient and model system triplets. By annotating with brain cell atlases from previous single-cell characterizations, 6 major clusters and over 20 sub-clusters of tumor cell states and hybrid states were identified. Overlaying results from bulk sequencing revealed cell state-specific expression of environment-induced programs. Further, these cellular state “niches” diverge in model environments suggesting that environmental factors modulate not only the composition of cellular states but also their biological roles within gliomas.
CSIG-15. ALTERATIONS IN THE TRANSSULFURATION PATHWAY ENABLE GLIOBLASTOMA INVASION INTO THE PERITUMORAL WHITE MATTER
Authors: Joseph Garcia, Saket Jain, Erin Akins, Angad Beniwal, Jordan Spatz, Sabraj Gill, Kayla Wolf, Junghwa Cha, Sanjay Kumar, Manish K Aghi
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is a primary malignant brain tumor with a median survival under two years. The poor prognosis glioblastoma caries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. While numerous factors have been proposed as the primary driving forces behind glioblastoma’s ability to invade adjacent tissues rapidly, little attention has been paid to the alterations in tumor cell metabolism needed for tumor cells to thrive in isolation in the peritumoral white matter. To improve on biased 2D cell culture studies, we defined the links between glioblastoma metabolism in invasion using unbiased CRISPR screens and metabolomics performed in biomimetic 3D hydrogels and regional biopsies of patient glioblastomas. Through these platforms, we identified targetable metabolic factors which drive cellular invasion in glioblastoma. Metabolomics revealed cystathionine to be selectively enriched in the invasive tumor front of both site-directed biopsies (6-fold change), and 3D organoid models (14-fold change). RNA sequencing revealed 7/30 (23%) metabolic genes upregulated in the invasive tumor front were involved in cysteine or glutathione metabolism. These results highlight a clear role of the transsulfuration pathway in glioblastoma invasion, revealing a targetable alteration unique to invading glioblastoma cells.
Healthcare professionals have a vital role to play in safeguarding older people from abuse
Authors: Caroline Abrahams
Journal: BMJ (2021)

Substantial numbers of older people experience financial, emotional, and physical abuse. Those with dementia and other health and care needs can be particularly at risk. It's surely equally obvious that older people can be both victims, and perpetrators, of domestic abuse, just like anyone else. Yet this is not something that’s talked about much—perhaps because older people have been largely absent from the official statistics on domestic abuse, since the data collection organised by the Office for National Statistics (ONS) in the ONS Crime Survey of England and Wales (CSEW) stops at age 74. At Age UK we thought this a flagrant example of ageism so we campaigned to change it. We were delighted when the ONS agreed earlier this year to remove this age limit from now on, because it should help us gain a better understanding of the nature and prevalence of domestic abuse among older people in this country.1 It should also shed some light on levels of domestic abuse in …
Abstract 10530: Stretch-Induced Arrhythmias Are Increased by Microtubule Detyrosination in a TRPA1 Dependent Manner in the Rabbit Heart
Authors: Jessi J Bak, T Alexander Quinn
Journal: Circulation (2021)

Introduction: Clinical evidence indicates that in hypertension, acute fluctuations in blood pressure can trigger ventricular arrhythmias. Single cell rabbit studies suggest that these stretch-induced arrhythmias (SIA) are related to increased microtubule (MT) density or detyrosination and depend on transient receptor potential ankyrin 1 channels (TRPA1). However, whether these mechanisms of SIA apply to the whole heart is unknown. Hypothesis: An increase in MT density or detyrosination will reduce the threshold for SIA in the whole heart and be dependent on TRPA1. Methods: Isolated rabbit hearts were instrumented with surface electrodes to monitor electrical activity and an intraventricular balloon to alter LV load. Transient changes in LV volume were applied to induce SIA (50-500μL, 10mL/s, 20 repetitions of each volume separated by 30s). SIA incidence vs volume was used to calculate the volume that resulted in a 50% SIA incidence (V 50 ). Paclitaxel (5μM) was applied alone to increase MT density and detyrosination or in combination with parthenolide (10μM) to prevent the increase in detyrosination or HC-030031 (10μM) to block TRPA1. Voltage optical mapping was used to determine the nature of SIA. MT density was assessed by immunofluorescence in isolated LV myocytes. Results: Paclitaxel reduced the threshold for SIA (decreased V 50 versus control: 133±16 vs 173±11μL; n =8 , p =0.02 by paired t-test) and resulted in the conversion of some stretch-induced ectopy to sustained activity. These effects were prevented by reduced detyrosination with parthenolide (262±27 vs 256±26μL; n =8 , p =0.75). Paclitaxel also increased MT density versus control, however this was not prevented by parthenolide (63±3 and 60±3 vs 50±4%; n =15, p =0.04 by one-way ANOVA). The decreased V 50 and occurrence of sustained arrhythmias with paclitaxel was also prevented by TRPA1 block with HC-030031 (249±26 vs 237±27μL; n =8, p =0.60). Optical mapping revealed stretch-induced ectopic excitation originating from the LV freewall, which resulted in re-entrant activity with paclitaxel. Conclusions: An increase in MT detyrosination leads to a reduced threshold for SIA and the triggering of sustained arrhythmias in the whole heart in a TRPA1 dependent manner.
Abstract 13386: Extracellular Matrix Signaling in Marfan Syndrome Induced Pluripotent Stem Cell Derived Smooth Muscle Cells
Authors: Alex R Dalal, Albert J Pedroza, Nobu Yokoyama, Ken Nakamura, Rohan Shad, Michael P Fischbein
Journal: Circulation (2021)

Introduction: Mutation in the extracellular matrix (ECM) protein fibrillin-1 lead to aortic root aneurysm in Marfan Syndrome (MFS). ECM composition influences vascular smooth muscle cell (SMC) phenotype, contractility, and signaling through mechanotransduction. Induced pluripotent stem cell-derived SMCs (iPSC-SMCs) are emerging as an attractive approach to model patient-specific vascular disease, but the use of iPSC-SMCs to investigate extracellular matrix biology remains limited. Hypothesis: Diseased MFS ECM induces phenotype modulation in healthy Control cells, while Control ECM will rescue contractile phenotype in MFS. Methods: Label-free mass spectroscopy core matrisome proteomic profiling of MFS and Control iPSC-SMCs from ammonia hydroxide decellularized ECM was performed. Decellularized ECMs were repopulated with MFS or Control iPSC-SMCs (N=3) (Figure A) and RNA extracted from whole cell lysate for RNA sequencing after four days of culture. Results: 24 core matrisome proteins were differentially expressed including overexpressed Collagen 1A1 and Tenascin C in MFS and enriched Thrombospondin 1 and Latent TGF-β Binding Protein 2 in Control (Figure B). Control iPSC-SMCs dramatically decreased contractile gene expression ( ACTA2 and CNN1 ) and ECM synthesis ( COL1A1 and FN1 ) when cultured on the diseased MFS ECM compared to the native Control ECM (Figure C). Conversely, the MFS cells expressed equally low contractile genes and the synthetic phenotype was exacerbated when cultured on the Control ECM (Figure D). Conclusions: Control iPSC-SMC mechanotransduction remains intact when interacting with the MFS ECM resulting in phenotype modulation into a MFS-like cell. Irreversible reprogramming of the MFS iPSC-SMC prevents rescue of the contractile phenotype when grown on a healthy ECM, despite the absence of MFS specific matrisome proteins. The decellularized iPSC-SMC ECM system effectively captures cell-ECM interactions and signaling.