tbuckley/cabot-search huggingface dataset:
Abstract 11604: The Cincinnati Atrial Fibrillation Score (CAFS): Multi-Center Derivation of the First Polysomnography-Based Risk Scoring System for Predicting Incident Atrial Fibrillation in Asymptomatic Community Adults
Authors: Rithika Thirumal, Benjamin Vaughan, Swati Dey, Anna Vogel, Worawan B Limpitikul, Miguel Dorante, Eliseo Guallar, Naresh M Punjabi, Steven R Jones, Deeptankar Demazumder
Journal: Circulation (2021)

Introduction: Early diagnosis of atrial fibrillation (AF) leading to early therapy can improve clinical outcomes (e.g., stroke). Current approaches for AF risk stratification are limited. Dynamic ECG analysis during sleep is an alternate, underexplored approach for AF risk stratification. Hypothesis: Dynamic ECG analysis during sleep predicts AF incidence in community adults, and adds major independent prognostic value to conventional AF risk factors and scores. Methods: In the multi-center prospective Sleep Heart Health Study, we studied consecutive, asymptomatic, ostensibly healthy, middle-aged and older community adults without a history of AF who were in sinus rhythm during home polysomnography. We performed comprehensive and systematic univariate and multivariate analyses of all available clinical, ECG and polysomnography parameters for association with AF incidence over follow-up. Results: Over 5.3±0.29 years, 315 (11.2%) of 2,807 people had new onset AF. We identified the major independent significant AF predictors, including established risk factors and ECG dynamics, and derived a multivariate prediction model entitled, the Cincinnati AF score (CAFS) ( FIGURE 1 ). Addition of CAFS to a multivariate model with (1) CHA 2 DS 2 -VASc score increased ROC curve area by 9% and yielded net reclassification improvement (NRI) of 90% [43+47% for cases and non-cases, respectively]; or with (2) CHARGE-AF score increased ROC curve area by 3.5% and yielded NRI of 54% [23+31%]. These improvements were driven primarily by the ECG dynamics, independent of sleep apnea and other risk factors. Conclusion: Dynamic ECG analysis during sleep adds major independent prognostic value to established AF risk factors and scores. The ability to better identify individuals who will and will not develop AF has potential for broad clinical impact. We are currently validating CAFS in another multi-center cohort of asymptomatic ambulatory adults with a diverse demographic profile.
EXTH-48. NOVEL COMBINATION THERAPY IN PRECLINICAL GLIOMA MODELS USING THE CELL CYCLE STABILIZING COMPOUND ARGYRIN F AND CHECKPOINT INHIBITION
Authors: Bianca Walter, Denis Canjuga, Simge G Yuez, Michael Ghosh, Przemyslaw Bozko, Justyna Przystal, Parameswari Govindarajan, Nicole Anderle, Anna-Lena Keller, Marcos Tatagiba, Katja Schenke-Layland, Hans-Georg Rammensee, Stefan Stevanovic, Nisar P Malek, Christian Schmees, Ghazaleh Tabatabai
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma are incurable aggressive tumors and remain a therapeutic challenge. Glioblastoma frequently harbor alterations in the retinoblastoma pathway with subsequent cell cycle abnormalities. Here, we aimed to investigate the anti-glioma activity of the cell cycle-stabilizing compound Argyrin F and its potential treatment-induced vulnerabilities to exploit possibilities for novel combination therapies. We investigated cell viability, clonogenic survival, cell cycle status and immunoblots of human and murine glioma cells treated with Argyrin F. Moreover, we established an ex vivo glioma model using residual freshly resected tissue from patients, i.e. patient-derived microtumors (PDMs). Additionally, we extracted autologous tumor infiltrating lymphocytes (TILs) to perform co-culturing experiments. We performed mass spectrometry-based immunopeptidomics and used the orthotopic syngeneic SMA560/VM/Dk glioma mouse model. Argyrin F displayed anti-glioma efficacy in glioma cell lines in vitro and in PDM models ex vivo. Moreover, Argyrin F treatment induced cell cycle arrest, reduced clonogenic survival in vitro and prolonged survival in vivo. Argyrin F-treated SMA560 glioma displayed 4.6-fold more glioma-infiltrating CD8+ T cells. We discovered a distinctive treatment-induced immunopeptidome. Combination of Argyrin F plus PD-1 antibody increased cellular toxicity in PDM/TILs co-cultures ex vivo and prolonged overall survival compared with monotherapies in vivo. We conclude that our experimental data suggest a novel combination of Argyrin F plus PD-1 blockade and its clinical translation.
Fluvoxamine for the Early Treatment of SARS-CoV-2 Infection: A Review of Current Evidence
Authors: Shelley N. Facente, Angela M. Reiersen, Eric J. Lenze, David R. Boulware, Jeffrey D. Klausner
Journal: Drugs (2021)

SARS-CoV-2 infection causes COVID-19, which frequently leads to clinical deterioration and/or long-lasting morbidity. Academic and governmental experts throughout the USA met in 2021 to discuss the potential for use of fluvoxamine as early treatment of SARS-CoV-2 infection. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is a strong sigma-1 receptor agonist, and this may effectively reduce cytokine production, preventing clinical deterioration. This repurposed psychiatric medication has a well-known safety record, is inexpensive, easy to use, and widely available, all of which are advantages during this global COVID-19 pandemic. At the meeting, experts reviewed the existing published literature on the use of fluvoxamine as experimental COVID-19 treatment, as well as prior research on the potential mechanisms for anti-inflammatory effects of fluvoxamine, including for other conditions including sepsis. Investigators shared current trials underway and existing gaps in knowledge. Two randomized controlled trials and one observational study examining the effect of fluvoxamine in COVID-19 treatment have found high efficacy. Four larger randomized clinical trials are currently underway, including three in the USA and Canada. More data are needed on dosing and mechanisms of effect; however, fluvoxamine appears to have substantial potential as a safe and widely available medication that could be repurposed to ameliorate serious COVID-19-related morbidity and mortality. As of April 2021, fluvoxamine was mentioned in the NIH COVID-19 treatment guidelines, although no recommendation is made for or against use. Available data may warrant clinician discussion of fluvoxamine as a treatment option for COVID-19, using shared decision making.
EPCO-22. INHERITED POLYMORPHISM IN CHROMOSOME 8Q24 COOPERATES WITH MUTANT IDH1, Trp53 AND ATRX LOSS TO INDUCE LOW-GRADE GLIOMA
Authors: Connor Yanchus, Kristen Drucker, Thomas Kollmeyer, Alexej Abyzov, Daniel Lachance, Jeanette Eckel-Passow, Tak Mak, Michael Taylor, Gelareh Zadeh, Peter Dirks, Robert Jenkins, Daniel Schramek
Journal: Neuro-Oncology (2021)

Abstract Establishing causal links between genetic polymorphisms and increased heritable risk of developing brain cancer is a major challenge. The non-coding single nucleotide polymorphism rs55705857 (A &amp;gt;G) is associated with a ~6-fold increased risk to develop IDH-mutant low-grade glioma (LGG). The rs55705857 G allele has a minor allele frequency of only ~5% in the general population but is found in ~40% of patients with IDH-mutant LGG and patients carrying risk-alleles are diagnosed on average 7-12 years earlier than those carrying non-risk A alleles. This makes rs55705857 one of the highest reported genetic associations with cancer, comparable with inherited BRCA1 gene mutations and the risk of developing breast cancer or other familial glioma genes such as NF1/2, CDKN2A or p53. To generate a LGG mouse model, we combined clonal activation of IDH1R132H with mutations of Trp53 and Atrx, which resulted in the development of LGG-like brain tumors in 25% of mice. Mutating the highly conserved, orthologous mouse rs55705857 locus to mimic the human risk allele dramatically accelerated tumor development from 463 to 172 days and increased penetrance to 75%. The resulting tumors exhibit elevated R-2-hydroxyglutarate levels, well-differentiated fibrillary neoplastic histology and metabolic rewiring, recapitulating histopathological and molecular hallmarks of human LGG. Mechanistically, we show that the rs55705857 locus resides within a brain-specific enhancer, which shows enhanced activity in IDH-mutant tumors. In addition, we found that the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. The hyperactive chromatin status combined with the tissue specificity of this enhancer explains the cooperativity between mutant IDH and rs55705857 and why rs55705857 is associated specifically with IDH-mutant glioma, but not other cancers. Overall, we generated new LGG mouse models, which provide insights into the pathophysiology of this deadly disease and shed light into the heritable predisposition to LGG development.
Abstract 10463: Angiotensin-Converting Enzyme 2 (ACE2) is Rate-limiting for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Infection in Beating Stem Cell-Derived Cardiomyocytes
Authors: Robyn G Macrae, Thomas L Williams, Maria T Colzani, Stuart Bloor, Jun Ru Zhan, Duuamene Nyimanu, Rhoda E Kuc, Janet J Maguire, Paul J Lehner, Sanjay Sinha, Anthony P Davenport
Journal: Circulation (2021)

Introduction: Cardiovascular comorbidities are a major risk factor in patients infected with SARS-CoV-2. SARS-CoV-2 Spike protein binds to host cell surface ACE2 to gain entry. ACE2 is subsequently downregulated by internalisation. We hypothesise that an ACE2 knockdown system in beating human embryonic stem cell-derived cardiomyocytes (hESC-CMs) will recapitulate the downregulation of ACE2, and reduce the ability of a SARS-CoV-2 Spike protein pseudotyped virus to infect these clinically relevant cells. Method: ACE2 was knocked down (KD) with CRISPR/Cas9 in hESCs, before differentiating to hESC-CMs and sub-culturing in 96 well plates. Sanger sequencing confirmed amino acid changes. Catalytic ACE2 activity was measured by mass spectrometry in wild-type versus KD by conversion of apelin-13 to apelin-12 in hESC-CMs supernatant. ACE2 activity was also measured by fluorescent substrate assay. Pseudotyped virus infection was visualised by high content screening in ACE2 KD versus wild-type (n=4). All data are mean±SEM. Results: Sequencing revealed two substitutions at ACE2 222-223 , and three deletions at ACE2 224-226 . This reduced ACE2 catalytic activity by ~60-70% by apelin-12 accumulation using mass spectrometry (Fig 1a), and fluorescent assay. Furthermore, KD reduced infection of hESC-CMs by pseudotyped virus to 27.3±9.6% of the cell population versus 74.8±4.7% for wild-type (Fig 1b,c). This is consistent with our previous data, showing DX600 (peptidic inhibitor of ACE2 catalytic site) significantly reduced infection of wild-type hESC-CMs to 20.5±6.5%. Conclusions: In conclusion, we generated a functional ACE2 knockdown in a beating cardiomyocyte cell model. Both the catalytic activity and the ability to bind SARS-CoV-2 Spike protein of ACE2 reduced, importantly indicating ACE2 is rate limiting for infection. We aim to use this system to further explore the cardiovascular consequences of SARS-CoV-2 infection and subsequent downregulation of ACE2.
DDRE-39. REPURPOSING CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS WITH GUIDANCE BY METHYLATION PROFILES
Authors: Anh Tran, Wenxia Wang, Denise Scholtens, Lyndsee Zhang, Jenny Pokorny, Yufen Wang, Aneta Baran, Felix Sahm, Kenneth Aldape, David James, Craig Horbinski
Journal: Neuro-Oncology (2021)

Abstract Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas are categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter or longer PFS at FDR-adjusted p &amp;lt; 0.05. Using Cytoscape/Reactome FI software, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the seventeen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. As monotherapy, the effects of docetaxel on meningioma were attenuated by multidrug resistance protein 1 (ABCB1) and Cytochrome P450 1B1 (CYP1B1). Docetaxel at 2µM augment double-stranded DNA damage caused by irradiation in vitro, leading to increased cell death. In animal model, low doses of docetaxel and radiation therapy had synergistic effects, increasing survival of mice intracranially implanted with human meningioma cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.
INNV-13. UNDERSTANDING FACTORS THAT INFLUENCE THE DECISION OF ACCEPTING TUMOR TREATING FIELDS (TTF) THERAPY
Authors: Priya Kumthekar, Madison Lyleroehr, Leilani Lacson, Roger Stupp, Rimas Lukas, Ray Lezon, Kellie Mora, Karyn Schmidt, Karan Dixit, Karen Kaiser
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Tumor Treating Fields (TTF) Therapy is an FDA-approved therapy in the first line and recurrent setting for glioblastoma. Despite Phase 3 evidence showing improved survival, it is not uniformly utilized despite its availability. This qualitative prospective study interviewed glioblastoma patients to better understand key driving factors for decision making. METHODS Adult glioblastoma patients who were offered TTF and who signed IRB approved consent were included. Patients participated in a one-time recorded interview with the researchers from the Northwestern University Department of Medical Social Sciences and were asked about factors shaping their decision to use or not use TTF. RESULTS 40 patients were enrolled with a mean age of 53 years, 92.5% were white and 60% were male. Of the 33 (82.5%) participants who accepted TTF, 23 (69.7%) reported their physician recommending TTF, 8 (24.2%) reported physician neutrality toward TTF, and 2 (6.1%) said their physician advised against TTF. Among the 7 (17.5%) participants who did not choose TTF, 4 (57.1%) reported physician neutrality, 2 (28.6%) reported that their physician advised against TTF, and 1 (14.3%) reported that their physician recommended TTF. Participants who decided against TTF stated that head shaving, appearing sick, and inconvenience of wearing/carrying the device most influenced their decision. For those choosing to use TTF, the most influential factors were extending life and following their doctor's opinion; other factors included level of familial support and the clinical evidence supporting TTF. DISCUSSION This clinical study was a collaboration with the Medical Social Sciences team to better understand the key factors that drive patient decision making with TTF. Findings suggest that physician support and positive Phase 3 results are among the key decision-making factors. Properly understanding the path to patients’ decision making is crucial in optimizing use of TTF and other therapeutic decisions for glioblastoma patients.
Viability of Chimeric Antigen Receptor T Cell Therapy in Latin America
Authors: Renato L Guerino-Cunha, Diego Clé, Leonardo Carvalho Palma, Camila Dermínio Donadel, Lucas Oliveira, Patricia Oliveira da Cunha Terra, Thalita Cristina de Mello Costa, Juliana Bernardes Elias Dias, Fabiano Pieroni, Ana Beatriz Pereira Lima Stracieri, Caio Raony Farina Silveira, Marcelo Lourencini Puga, Amanda Mizukami Martins, Sâmia Rigotto Caruso, Lucas Eduardo Botelho Souza, Daianne Maciely Carvalho Fantacini, Leticia Maria Defendi Barboza, Maria Fernanda Lima Giuberti, Gabriel Carvalho Pereira, Taisa Risque Fernandes, Rosane Maria Falasco Bolzoni, Ana Carolina Jesus Vieira, Patrícia Vianna Bonini Palma, Anibal Basile, Fernando Chahud, Benedito Pina Almeida Prado, Maristela Delgado Orellana, Gil Cunha De Santis, Eduardo M Rego, Rodrigo T. Calado, Dimas T. Covas
Journal: Blood (2021)
Abstract 12434: Long-Term Clinical Outcomes After Major versus Minor Bleeding in Patients With Atrial Fibrillation: The Fushimi AF Registry
Authors: Kenjiro Ishigami, Hisashi Ogawa, Syuhei Ikeda, KOSUKE DOI, Yasuhiro Hamatani, Yuya Ide, Akiko Fujino, MITSURU ISHII, Moritake Iguchi, Nobutoyo Masunaga, Masahiro Esato, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2021)

Introduction: Oral anticoagulants reduce the risk of ischemic stroke but may increase the risk of bleeding in atrial fibrillation (AF) patients. However, the clinical outcomes of patients after major or non-major bleeding are unknown. Methods: In the Fushimi AF Registry, follow-up data were available in 4,470 patients by the end of September 2020. Major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. We investigated the demographics and outcomes of AF patients who experienced major bleeding and clinically relevant non-major bleeding (CRNM) during follow-up period. Results: During the median follow-up period of 1,459 days, major bleeding and CRNM occurred in 350 (7.8%) and 719 patients (16.1%) as first bleeding event, respectively. Patients with major bleeding were older (major vs CRNM vs no-bleeding; 75.6 vs 73.9 vs 73.3, p=0.001), and more likely to have chronic kidney disease (44.6% vs 35.2% vs 35.1%, p=0.002), previous major bleeding (8.0% vs 3.5% vs 4.4%, p=0.006). Patients with major bleeding had higher CHADS 2 score (2.3 vs 2.0 vs 2.0, p&lt;0.001), higher CHA 2 DS 2 -VASC score (3.7 vs 3.4 vs 3.3, p=0.001), and higher HAS-BLED score (2.0 vs 1.8 vs 1.7, p&lt;0.001). On landmark analysis, all-cause mortality occurred in 137 patients after major bleeding (15.8 /100 person-years), 134 patients after CRNM (5.3 /100 person-years), and 803 patients without bleeding during follow-up period (5.2 /100 person-years) (hazard ratio [HR] 2.68, 95% confidence interval [CI] 2.24-3.22, p&lt;0.0001 [major bleeding vs. no-bleeding]; HR 0.97, 95%CI 0.81-1.17, p=0.761 [CRNM vs. no-bleeding]). (Figure) Conclusion: AF patients after major bleeding had significantly higher incidence of all-cause mortality, but those after CRNM did not have significant incidence of all-cause mortality in a community-based AF cohort.
Experiences With Genetic Counseling, Testing, and Diagnosis Among Adolescents With a Genetic Condition
Authors: Tasha Wainstein, Sheila K. Marshall, Colin J. D. Ross, Alice K. Virani, Jehannine C. Austin, Alison M. Elliott, Bartha Knoppers, Larry D. Lynd, Alivia Dey, Shelin Adam, Nick Bansback, Patricia Birch, Lorne Clarke, Nick Dragojlovic, Jan Friedman, Debby Lambert, Daryl Pullman, Wyeth Wasserman, Ma'n Zawati
Journal: JAMA Pediatrics (2021)

The number of adolescents who are diagnosed with a genetic disorder is increasing as genome sequencing becomes the standard of clinical diagnostic testing. However, the experience of receiving a diagnosis of a genetic condition has not been extensively studied in adolescents.To identify how adolescents with a genetic condition engage with genetic or genomic counseling services as well as interpret, adapt to, and experience their diagnosis.A literature search of MEDLINE, Embase, CINAHL, and PsycINFO was undertaken. Articles (primary literature, knowledge syntheses, and gray literature) in English that investigated the experiences of adolescents between 10 and 19 years of age who received genetic or genomic counseling were included. Data were extracted from 45 eligible articles and analyzed descriptively.A total of 45 studies were included, most of which were quantitative in nature (21 of 45 [47%]) and conducted in the US (n = 13), followed by the UK (n = 8), Australia (n = 8), and Canada (n = 6). A total of 29 distinct monogenic disorders were investigated. Sample sizes ranged from 1 to 930, with a median of 23 participants, and the year of publication ranged from 1977 to 2019. Included studies addressed all aspects of genetic counseling, but a preponderance of articles assessed knowledge about genetic conditions (n = 17) and challenges of communication within families (n = 16). Fewer articles addressed the experiences of adolescents adapting to their genetic conditions (n = 8) and the genetic counseling process (n = 4). Only 1 study addressed any aspect of genetic counseling in relation to genome sequencing.This scoping review found that most of the included studies focused on adolescents' knowledge about their genetic condition and communication about genetic risks, whereas fewer studies explored their adaptation to the condition and the genetic counseling process. A systematic reconsideration of the genetic counseling process may be undertaken to provide an evidence-informed health care service that is tailored to the needs of this adolescent population.
Abstract 10064: Pulmonary Hypertension in Patients with Connective Tissue Disease-associated Interstitial Lung Disease and Vascular Changes on Computed Tomography
Authors: Badar Patel, Sirus Jesudasen, Pietro Nardelli, Ruben San Jose Estepar, Kristin D'Silva, George Washko, Raul San Jose Estepar, Sydney Montesi, Farbod Rahaghi
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH) is a complication in patients with connective-tissue disease-associated interstitial lung disease (CTD-ILD) associated with mortality. In Idiopathic Pulmonary Fibrosis, increased vascular volume has been reported to be associated with poor outcomes. We sought to elicit whether similar changes could be observed in patients with CTD-ILD and pulmonary hypertension. Methods: We identified patients with a known diagnosis of CTD-ILD who had undergone chest CT, transthoracic echocardiography (TTE), and right heart catherization (RHC) using the Mass General Brigham Research Patient Data Repository (IRB #2018P000419). The electronic health records (EHR) were reviewed to confirm the diagnosis of CTD-ILD. A 3D reconstruction of the pulmonary vasculature using the Chest Imaging Platform ( www.chestimagingplatform.com ) to compute the total vascular volume was performed on thin sliced CT scans closest to the RHC. Vessels were separated into arterial and venous components using a deep learning approach. Statistical analysis was performed with R 4.01. Values are shown as medians and interquartile ranges and were compared using Wilcoxon Rank-Sum tests. Results: A total of 104 patients with CTD-ILD were identified: Pre-capillary PH (n=43), Isolated Post-capillary PH (n=9), Combined Pre- and Post-capillary PH (n=8), and PH Absent (n=44). There was no difference in patient age or lung volume by CT scan. On TTE, RVSP was elevated in PH (52 mmHg, IQR 41-64 mmHg vs 34 mm Hg, IQR 27-49 mmHg, p &lt; 0.0001), as was the arterial total vascular volume (118 mL, IQR 85-152 ml vs 100 mL, IQR 77-126 ml, p = 0.009) with no trend for significance for venous total vascular volume. Addition of total arterial volume remained a statistically significant predictor of presence of PH (p = 0.01) when added to logistic regression models predicting PH by TTE RVSP, with improvement in model AIC (106.1 to 97.9) and AUC (0.75 to 0.80) of the model. Conclusions: In this retrospective study of patients with CTD-ILD and available imaging and hemodynamics, patients with PH have increased arterial vascular volume compared to those without PH. Information derived from CT images routinely acquired in this population could be used to improve screening and phenotyping.