tbuckley/cabot-search huggingface dataset:
Abstract 9952: Periodontal Inflammation, Periodontal Bacterial Load and Virulence Genes Expression Are Risk Factors for Myocardial Infarction
Authors: Chaitanya Joshi, Alice Mezincescu, Maheshi Gunasekara, Amelia Rudd, Helene Botchorichvili, Suleman Sabir, Ciprian Dospinescu, Awsan Noman, George Cherukara, David McLernon, Karolin Hijazi, Dana Dawson
Journal: Circulation (2021)

Background: A causal relationship between periodontitis and Myocardial Infarction (MI) is stipulated but remains incompletely characterised. Methods: Prospectively recruited 160 acute MI patients underwent periodontal exam to quantify periodontal inflamed surface area (PISA), probing pocket depths (PPD) and clinical attachment loss (CAL). Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans and Prevotella intermedia loads were assessed in subgingival plaque, venous blood, aspirated intra-coronary thrombi and deployment balloons using quantitative polymerase chain reaction. Expression of periodontal bacterial virulence genes (n=13) was quantified with reverse transcription PCR. Myocardial injury was estimated by 12-hour troponin (TnI) and severity of coronary artery disease (CAD) burden by SYNTAX-I scores. CAD-symptom free controls (n=50) of similar age/gender distribution were used for comparison. Results: Compared to controls, MI patients had worse periodontitis and higher bacterial loads (all p &lt;0.05). In MI cohort, after adjusting established risk factors, hierarchical linear regression showed that PISA (5%), mean PPD (3%), mean CAL (2%), P. gingivalis load (4%) and upregulated expression of bioF-3 , fimA , prtH , prtP , ltxA , cdtB virulence genes (4-9%) were associated with an increase in Tnl release, all p &lt;0.05. Similarly, mean PPD (5%), mean CAL (4%), P. gingivalis load (5%) and upregulated expression of bioF-3 , fimA , prtP and ltxA virulence genes (4-9%) were associated with higher SYNTAX-I score, all p &lt;0.05. Every 200 mm 2 PISA, 1mm mean PPD, 1mm mean CAL and 10 9 P. gingivalis copies/ng DNA was responsible for 19,000, 32,000, 38,000 and 10,000 ng/L increase in TnI release, respectively. The SYNTAX-I score increased by 3, 4 and 1 unit with every 1mm mean PPD, 1mm mean CAL and 10 9 P. gingivalis copies/ng DNA, respectively. Periodontal bacterial DNA was detected in coronary thrombi and subgingival plaque sampled from the same patients, with a strong correlation for P. gingivalis and T. forsythia bacterial loads (Spearman's rho=0.6 for both, p &lt;0.05). Conclusions: These findings enable further recognition of periodontitis as a risk factor for MI; a new candidate for primary and secondary prevention.
Abstract P303: Development Of <i>Casper/myl7/annexin-5</i> Transparent Transgenic In-vivo Zebrafish Model To Study The Cardiomyocyte Function
Authors: Surendra K Rajpurohit, Aaron Gopal, May Y Mon, Nikhil Patel, Vishal Arora
Journal: Circulation Research (2021)

The Zebrafish provided an excellent platform to study the genetic and molecular approach ofcardiac research. Zebrafish heart cells similar to human heart cells at the molecular level anddetermine gene functions that control cardiac function and dysfunction. In zebrafish heart, myl7is myosin 7 gene and identified as a regulatory gene orthologs to human MYL7. In the heart,Annexin5 activities contribute to cardiomyocyte dedifferentiation, proliferation and epicardial injuryresponses which leads to cardiac cell death by apoptosis and narcosis pathways. We aredeveloping annexin-5 activity in the cardiovascular function under normal and in metabolicaberration by generating homozygous Casper/ myl7:RFP; annexin-5:YFP transgenic zebrafish.By developing Casper/myl7/Annexin-5 transparent transgenic zebrafish model, we establish time-lapse in-vivo confocal microscopy to study of cellular phenotype/pathologies of thecardiomyocytes over time in newly developed strain to quantify changes in cardiomyocytemorphology and function overtime, comparing control and cardiac injury and cardio-oncologymodels. Transgenic zebrafish has normal type skin pigmentation background. In zebrafish,tracking of transgenic reporter activity in in-vivo is only possible in transparent stage. To maintaintransparency throughout the life, these strains crossbred with the skin transparent mutant Casper.Casper contributes to the study by integrating a transparent characteristic in adult zebrafish thatallows for simpler transparent visualization and observation. We develop casper transgenicprogenies through cross breeding with the transgenic strain of myl7:RFP;annexin-5:YFP .Confocal and fluorescent microscopy used to get accurate, precise imaging and to determinefluorescent protein being activated. 1.1: Generation of homozygous casper / myl7:RFP;annexin-5:YFP zebrafish (Generation F01-F05). 1.2: Screening and sorting the transgenic progeny andIn vivo imaging to validate cardiac morphology through in-vivo confocal imaging. Generation ofhomozygous casper / myl7:RFP;annexin-5:YFP zebrafish: Casper-Annexin5 homozygous stain:Cross breed casper and myl7/Annexin5 fish; F01: Generate the eggs from breeder and grow theembryo to attenuate larvae to screen for transgenic expression. F01 generation, larvae showtransgenic expression (47%). F02: transgenic expression larvae (39%). F02 heterozygous shownormal skin pattern; F03, larval show transgenic expression (43%). F04, transgenic larvae(90%).F04; 100% fishes are phenotypically casper; F05: heterozygous transgenic progeny togrow and continue to generate until achieve 100% homozygous casper-myl7-Annexin5 strain.These novel results provide in-vivo whole organism-based platform to design high throughputscreening and establish new horizon for drug discovery in the Cardiac Disease and Cardio-oncology.
PATH-20. SPATIAL MAPPING OF THERAPY-INDUCED, PATHOLOGICAL CHANGES IN GLIOBLASTOMA AT SINGLE-CELL RESOLUTION
Authors: Maxime Vanmechelen, Jan Beckervordersandforth, Jon Pey, Asier Antoranz, Pouya Nasari, daniele Pantano, Sien Bevers, Daphne Leunissen, Wout Moors, Julie Messiaen, Ivey Sebastian, Giorgia Milli, Yannick Van Herck, Emma Geens, Maikel Verduin, Linde Hoosemans, Annelies Claeys, Marleen Derweduwe, Axel Zurhausen, francesca Bosisio, Danielle Eekers, Frank Weyns, Thomas Daenekindt, Peter Van Eyken, Mark Goovers, Koos Hovinga, Steven De Vleeschouwer, Paul Clement, Martijn Broen, Marc Vooijs, Raf Sciot, Ann Hoeben, Ernst Jan Speel, Frederik De Smet
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) remains a highly malignant, intrinsically resistant and inevitably recurring brain tumor with dismal prognosis. The aggressiveness and lack of effective GBM treatments can be attributed to the highly heterogeneous and plastic nature of GBM tumor cells, which easily confer resistance to standard-of-care (SOC) therapy. While tumor progression has also been attributed to interactions with the tumor microenvironment, quantitative data describing these interactions are still largely missing. Here, we used high-dimensional, multiplexed immunohistochemistry to map evolutions in the spatial, single-cell tissue architecture of 120 paired adult GBM tumor samples derived from 60 patients at diagnosis (ND) and upon recurrence (REC) following SOC treatment. We mapped the spatial distribution of a multitude of GBM tumoral subtypes across this multicentric cohort, through which we identified a high level of heterogeneity defined by specific tumoral niches within and across patients and which evolved when subjected to SOC therapy. In addition, we describe the relationship of the various tumoral niches with their local immune-infiltrates, highlighting an even more immunosuppressive environment following SOC resistance. Finally, by aligning these findings to the observed genomic aberrations and the clinical data of the patients, we are now able to more precisely describe the heterogeneous landscape of glioblastoma and how it evolves under SOC treatment at spatial, single-cell resolution.
Myelodysplastic Syndromes: Have You Seen Your Patient Beyond His Hemoglobin?
Authors: Raíssa Pires Camargo Ebert, Mariana Munari Magnus, Cristina Bueno Terzi, Antonio Luis Eiras Falcão, Fernando Ferreira Costa, Sara T Olalla Saad, Paula De Melo Campos
Journal: Blood (2021)
Robust IgM responses following intravenous vaccination with Bacille Calmette–Guérin associate with prevention of Mycobacterium tuberculosis infection in macaques
Authors: Edward B. Irvine, Anthony O’Neil, Patricia A. Darrah, Sally Shin, Alok Choudhary, Wenjun Li, William Honnen, Smriti Mehra, Deepak Kaushal, Hannah Priyadarshini Gideon, JoAnne L. Flynn, Mario Roederer, Robert A. Seder, Abraham Pinter, Sarah Fortune, Galit Alter
Journal: Nature Immunology (2021)

Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). Intravenous (i.v.) vaccination with Bacille Calmette-Guérin (BCG) provides nearly complete protection against TB in rhesus macaques, but the antibody response it elicits remains incompletely defined. Here we show that i.v. BCG drives superior antibody responses in the plasma and the lungs of rhesus macaques compared to traditional intradermal BCG administration. While i.v. BCG broadly expands antibody titers and functions, IgM titers in the plasma and lungs of immunized macaques are among the strongest markers of reduced bacterial burden. IgM was also enriched in macaques that received protective vaccination with an attenuated strain of Mtb. Finally, an Mtb-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and mediator of protection against TB.
QOLP-26. ANALYSIS OF REDDIT USERS' PERSPECTIVES OF BRAIN TUMORS
Authors: Sanidhya Tripathi, Arpan Prabhu, Kevin Thomas, Pearman Parker, Analiz Rodriguez
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Reddit, ranking 6th in worldwide Internet site traffic, is a commonly used forum among patients and caregivers affected by brain tumors to discuss diagnoses, treatment, and self-care management. The use of the online forum may suggest patients and caregivers have unmet needs and are seeking further support outside of the clinical setting. We aimed to examine trends from Reddit discussion treads on brain tumors to identify areas of need in patient care. METHODS We used a qualitative, descriptive design to understand patient and caregivers unmet and met needs. We analyzed the top 100 posts and accompanying 271 comments from the ‘braincancer’ subreddit to identify common themes. RESULTS The qualitative content analysis revealed three major topic areas: (1) moving through the grief process; (2) processing diagnostic pathway; and (3) expressing gratitude toward other Reddit users. Most of the authors of the posts were patients with brain tumors (n = 32; 38.5%) who used Reddit as a reflective journaling tool to move through the grief process for themselves or loved ones. About 47% of theses posts discussed the diagnostic process of glioblastoma multiforme (GBM) brain tumors, where users requested an inclusive/welcoming environment in the clinic by their healthcare professionals (HPs). Users also solicited and gave support for other members in the online community. CONCLUSIONS This study highlights the need of implementing social media as a part of HPs’ repertoire for patient outreach/needs. Furthermore, social media outlets like Reddit can help HPs understand the level of support they can give to their patients. Plans of action for physicians seeking to meet the needs of brain tumor patients include monitoring the concerns of patients, becoming verified on the platform/openly identifying themselves online, or conducting ‘Ask Me Anything’ discussions to educate patients.
STEM-12. THE SMALL MOLECULE DRUG CBL0137 INCREASES THE LEVEL OF DNA DAMAGE AND THE EFFICACY OF RADIOTHERAPY FOR GLIOBLASTOMA
Authors: Miranda Tallman, Abby Zalenski, Amanda Deighen, Treg Grubb, Morgan Schrock, Sherry Mortach, Preetham Kastury, Kristin Huntoon, Matthew Summers, Monica Venere
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is a fatal and incurable brain tumor, with an average life expectancy after diagnosis of only 12-15 months. A main reason for the lethality of GBM is inevitable recurrence, caused by a small population of the tumor cells, called cancer stem cells (CSCs). These cells are aggressive, infiltrative, and resistant to current GBM treatments of chemotherapy and radiotherapy. We use a small molecule drug, CBL0137, which inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy and hence lead to increased CSC death and prolonged survival in preclinical models. Clonogenic assays were used to show that CSCs were radiosensitized after CBL0137 treatment. We saw increased DNA damage when GBM CSCs were treated with CBL0137, as well as a decrease in foci resolution over time, when CBL0137 was combined with irradiation. In order to elucidate if the increase in DNA damage was directly due to the inhibition of the FACT complex, we depleted the level of FACT in our GBM CSCs. FACT depletion also led to increased DNA damage, and even more so when combined with irradiation. To validate whether combination therapy sensitized CSCs to radiotherapy in vivo, we used a subcutaneous mouse model and showed combination treatment decreased CSCs frequency in these tumors as well as decreased tumor volume. With an orthotopic model of GBM, we showed that CBL0137 treatment followed by radiotherapy significantly increased survival of mice bearing tumors over either treatment alone. Together, this work establishes a new treatment paradigm for GBM, which sensitizes radio-resistant GBM CSCs to irradiation, a critical component of patient care. Radio-sensitizing agents, including CBL0137, pose an exciting new therapeutic capable of increasing the efficacy of irradiation, by inclusively targeting CSCs.
Abstract 10697: Both ST2 and BNP Predicts Atrial Fibrillation Independently of Heart Failure but BNP is Stronger When Used in Combination
Authors: Kamla Al-Wahaibi, Iftikhar Khan, Brendan F McAdam, Tora Leong
Journal: Circulation (2021)

Background: ST2, a novel marker of fibrosis in heart failure, may be a marker in Atrial fibrillation (AF) due to the role of fibrosis in AF. There is paucity of data suggesting the association of ST2 with AF. Hypothesis: To examine the association of ST2 with AF and its incremental value over traditional biomarkers. Methods: 619 unselected patients presenting to a Cardiology service had BNP and ST2 sent. They included patients with heart failure, acute coronary syndromes, elective cardioversion for AF and cardiac catheterisation. Results: Their characteristics are shown in Table1. Both ST2 and BNP levels were significantly higher in patients with heart failure, chronic kidney disease (CKD) and AF. The AF group (30%) were older and had higher prevalence of heart failure and CKD. Both ST2 and BNP were associated with AF in both univariable (Table 2) and multi-variable models, and remained independent predictors when adjusted for risk factors (Table 3 Model 2). However, ST2 loses significance when BNP is added to the model (Table 2 Model 3). While ST2 levels were significantly higher in males, there was no significant interaction when stratified by sex (interaction p=0.31). Conclusions: Both ST2 and BNP are independent predictors of AF even after adjustment for other clinical factors. When ST2 is used in combination with BNP, raised BNP appears to be a stronger predictor of AF than ST2.
Abstract 11752: Pitavastatin Treatment Ameliorates HIV-Nef Containing Extracellular Vesicle-Mediated Cardiomyocyte Dysfunction
Authors: Sarvesh Chelvanambi, Julius Decano, Shiori Kuraoka, Elena Aikawa, Sasha A Singh, Masanori Aikawa
Journal: Circulation (2021)

Rationale: The prevalence of cardiovascular diseases such as heart failure and left ventricular diastolic dysfunction remains high in People Living With HIV (PLWH) even with the advent of modern anti-retroviral therapy (ART). Sustained plasma persistence of the pro-inflammatory HIV protein Nef within extracellular vesicles (EV) of ART-treated patients may contribute to continued disease progression. We hypothesized that HIV-Nef induces cardiomyocyte dysfunction by elevating Reactive Oxygen Species (ROS) production which then increases apoptosis and senescence in cardiomyocytes. Results: Network analysis using Metacore of cytosolic and nuclear proteomics of human cardiomyocytes stimulated with HIV-Nef EV demonstrated changes in metabolic processes, DNA damage, oxidative stress and cytoskeletal remodeling. HIV-Nef EV promotes cardiomyocyte cellular dysfunction as evidenced by increased ROS production, DNA damage, apoptosis and premature senescence in both AC-16 cardiomyocyte cell line (n=5, p&lt;0.001) and iPSC-derived cardiomyocytes (n=4, p&lt;0.01). HIV-Nef EV stimulation induced cardiomyocyte metabolic switch by increasing consumption of anaerobic substrate (Lactic Acid) and decreasing consumption of TCA substrate (Citric Acid). [AE1] Network-science powered pathway analysis of HIV-Nef EV stimulated cardiomyocytes identified a key hub in Rac1-GTPase mediated pathways. Proteomic analysis of HIV-Nef transfected HEK293T cells indicated pitavastatin treatment altered Rac1 trafficking to inhibit interaction with HIV-Nef, suggesting a potential protective mechanism. Subsequently, cardiomyocyte dysfunction was abrogated by clinically relevant doses of pitavastatin (10-100nM ,n=4, p&lt;0.01). Addition of HIV-Nef EV supernatant to AC-16 cardiomyocytes but not to those treated with pitavastatin increased chemotaxis of primary human macrophages (n=4, p&lt;0.05). Conclusion: Pitavastatin treatment may prevent Nef EV-mediated cardiac dysfunction and inflammation in HIV patients. [AE1]I suggest including numbers of technical or biological replicates and p values when possible.
Complex Structural Variation Associated with Enhancer Hijacking and Loss of Tumor Suppressors in Mantle Cell Lymphoma
Authors: Prasath Pararajalingam, Laura K Hilton, Krysta M. Coyle, Kostiantyn Dreval, Barbara Meissner, Ari Melnick, Marco A. Marra, David W. Scott, Ryan D Morin
Journal: Blood (2021)
Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis
Authors: Omar Albanyan, Hyejeong Jang, Seongho Kim, Andrew Kin, Asif Alavi, Lois Ayash, Voravit Ratanatharathorn, Dipenkumar Modi, Joseph P. Uberti, Abhinav Deol
Journal: Blood (2021)
Abstract P507: Comprehensive Characterization Of Poly(a)-clickseq Data Sets Reveal Novel Polyadenylation Signals In Human Right Ventricle Failure
Authors: Rajarajan A Amirthalingam Thandavarayan, Hari Krishna Yalamanchili, Rajasekaran Mahalingam, Scott D Collum, Keith Youker, Eric Wagner, Arvind Bhimaraj, Harry Karmouty-quintana, Ashrith Guha
Journal: Circulation Research (2021)

Background: Many human genes hold more than 1 poly(A) site, and polyadenylation gives rise to transcripts with different 3′ untranslated regions (3’UTR) lengths, and this process known as alternative polyadenylation (APA). It plays a significant role in many cellular processes and dysregulation of APA leads to many human diseases. However, the functional consequences of APA events in the right ventricle (RV) failure in humans remain unexplored. Objective: To understand whether a global APA event is presented in the progression of RV failure by using the novel algorithm PolyA miner in the RV of healthy donors and patients with RV failure. Methods and Results: RV tissue samples were obtained from failing human hearts at the time of cardiac transplantation at the Houston Methodist DeBakey Heart &amp; Vascular Center, Houston Methodist Hospital. The RV tissues were immediately frozen in liquid nitrogen and stored at –80°C until use. Normal tissue samples were obtained from donor hearts that were not used for transplantation and were collected and stored in the same manner. We characterized the APA profiles of RV failing patients and compared them to healthy RV specimens by using Poly(A)-ClickSeq (PAC-seq) RNA sequencing and the PolyA-miner algorithm. We determined shortening versus lengthening of 3′UTRs based on the PolyA index, a metric unit that determines the length of 3′UTR. Based on these scores, we identified 435 transcripts with a significant shift in cleavage site usage. Further, we discovered 3'UTR shortening and lengthening of many genes in failing RV compared to healthy RV specimens. By examining polyadenylation events in these hearts, we identified disease-specific APA signatures in many genes. In addition, differential APA events in RV failure regulate many pathways important for the progression of the RV failure. Conclusions: Our study highlights the important roles for APA in human RV failure, including reforming multiple pathways and regulating specific gene expression, representing the complex interplay between APA and other biological processes in the RV failure.
Abstract 14144: Reproducibility of Myocardial Blood Flow Quantification With Low-Dose CT
Authors: Sabee Molloi, Yixiao Zhao, Negin Hadjiabdolhamid, Logan C Hubbard
Journal: Circulation (2021)

Introduction: Dynamic CT perfusion can be used for physiological assessment of coronary artery disease. However, it is limited by its high radiation dose and limited reproducibility. Hypothesis: A single-volume myocardial CT perfusion technique can reproducibly measure myocardial blood flow in mL/min/g at a low radiation dose. Methods: The reproducibility of a single-volume myocardial CT perfusion technique was assessed in 4 swine (54.5 ± 1.9 kg) under rest and stress (IV adenosine: 240 μg/mg/kg/min) conditions. Thirteen pairs of repeated CT measurements were made, with a 20-minute delay between each acquisition. Contrast (0.7 mL/kg; 370 mgI/mL) and saline chaser (0.35 mL/kg) were injected peripherally, each at 5 mL/s, followed by bolus tracking and acquisition of a single volume scan at 100 kVp and 200 mA with a 320-slice CT scanner. The timing for acquisition of the single volume scan was determined based on the contrast injection time. The bolus tracking and single volume scan data were then used as analytical inputs into a novel first-pass analysis model to derive perfusion in mL/min/g. The coronary artery centerlines from the volume scan were used for automatic assignment of the left anterior descending (LAD), left circumflex (LCx) and right coronary artery (RCA) perfusion territories. The reproducibility of myocardial blood flow measurement in each territory was then assessed via regression analysis. Results: The first (P PRO1 ) and second (P PRO2 ) prospective single-volume CT perfusion measurements were related by P PRO2 = 1.04 P PRO1 - 0.05 (Pearson’s r = 0.99; RMSE = 0.24 mL/min/g). The average CT dose index of the technique was only 140.3 mGy. Conclusions: The single-volume quantitative CT perfusion technique provides low-dose, reproducible, myocardial perfusion measurement in mL/min/g using only bolus tracking data and a single whole-heart volume scan. The technique can also provide simultaneous CT angiogram when acquired with appropriate radiation dose.