tbuckley/cabot-search huggingface dataset:
Abstract 9828: Active Surveillance of Cardiotoxicity with Cardiac Biomarkers During Chimeric Antigen Receptor T-Cell Therapy
Authors: Dae Hyun Lee, Sanjay Chandrasekhar, Michael Jain, Julio Chavez, Bijal Shah, Aleksandr Lazaryan, Farhad Khimani, Taiga Nishihori, Christina Bachmeier, Michael Fradley, Daniel Jeong, Frederick L Locke, Guilherme Oliveira, Mohammed Alomar
Journal: Circulation (2021)

Introduction: Chimeric Antigen receptor T- Cell (CAR-T) immunotherapy has been a breakthrough for various hematological malignancies. Cardiotoxicites such as heart failure, arrhythmia and acute coronary syndrome occur in approximately 1/3 of patients who develop cytokine release syndrome (CRS) following CAR-T. High grade CRS (Grade ≥ 2) and elevated troponin level are associated with increased risk of cardiotoxicity. It is unclear whether active cardiotoxicity surveillance with serial cardiac biomarker measurements during CAR-T would allow early detection of cardiotoxicity. Methods: This was retrospective cohort study involving patients diagnosed with non-Hodgkin lymphoma treated with CAR-T therapy (Axicabtagene ciloleucel- Yescarta, tisagenlecleucel- Kymriah, Brexucabtagene autoleucel- Tecartus). Baseline cardiac workup with electrocardiogram (ECG), transthoracic echocardiogram (TTE), troponin (Reference &lt;0.03ng/mL), B-natriuretic peptide (BNP, &lt;100pg/mL) were uniformly performed in all participants. Follow up ECG, Troponin and BNP were obtained at day 5 after CAR-T and at development of CRS Grade ≥2. When clinically indicated, cardiac MRI with gadolinium contrast was performed. Cardiac MRI diagnosis of myocarditis was based on Lake Louise Criteria. Results: A total of 47patients undergoing CAR-T therapy were studied. Baseline comorbidities were not predictive of CRS or cardiac events. There were 39 patients with low grade CRS (82.9%) and 8 patients (17.0%) with grade 2 CRS. Five patients had elevated troponin I levels (Grade 1 CRS - 3; Grade 2 CRS - 2). Cardiac MRIs were performed in three patients (two normal studies, one with mild myocarditis). Five patients (10.6%) had an adverse cardiac event (Myocarditis with heart failure - 1; new-onset atrial fibrillation - 3; Type 2 myocardial infarction -1). Conclusion: Adverse cardiac events are a relatively common occurrence in patients receiving CART therapy. Active surveillance for cardiotoxicity using cardiac biomarkers in CAR-T patients may play an adjunctive role in the early identification of adverse cardiac events. Larger studies are needed to adjudicate the use of such screening measures in these high-risk patients.
Abstract 12288: Three-Dimensional Location and Heatmap Distribution of Frame Fractures on the GORE Cardioform ASD Device
Authors: Gareth J Morgan, Salvador A Rodriguez Franco, Ryan Leahy, Jess Randall, Jenny E Zablah
Journal: Circulation (2021)

Objective: To evaluate the frequency and characteristics of Gore Cardioform ASD Device Frame Fractures (FF) and explore potential associations in patient and procedural practice variables. Background: The latest device approved by the FDA for atrial septal defect (ASD) closure is the GORE® Cardioform ASD occluder (GCA). Despite a very low incidence of complications having a direct impact on patient wellbeing, a significant amount of FFs have been observed in the GCA at short to medium-term follow-up, being described in almost one-third of the devices implanted during clinical trials. Methods: We performed a retrospective single-center chart review of 54 patients who received a GCA between January 2017 and December 2019, and selected 35 patients in whom a 6-month fluoroscopic follow-up was performed. We evaluated the number and type of fractures based on this fluoroscopic assessment and devised a simple nomenclature system based on three-dimensional (3D) reconstruction of the device's fluoroscopic images. We also evaluated the association between the position and number of fractures, and patient and procedural characteristics. Results: The FF incidence in our population was 42.9% at a 6-month follow-up. The factors statistically associated with FF were the size of the defect and the size of the device implanted. FFs were most frequently located in a central position in the right atrial disc. By 3D evaluation, the most common anatomical position for fractures was the anteroinferior quadrant of the right atrial disc. At the time of manuscript submission, no echocardiographic or clinical sequelae were noted in our population. Conclusions: The incidence of frame fractures in our population was higher than that observed in published literature, albeit using more intense image scrutiny than that required by other cited studies. We noted that the central portion of the anteroinferior quadrant of the right atrial disc was the most susceptible to FF and found that the defect size and the device size were the only statistically associated factors.
Investing in trust and community resilience: lessons from the early months of the first digital pandemic
Authors: Salma M Abdalla, Shaffi Fazaludeen Koya, Margaret Jamieson, Monica Verma, Victoria Haldane, Anne-Sophie Jung, Sudhvir Singh, Anders Nordström, Thoraya Obaid, Helena Legido-Quigley, Christine McNab
Journal: BMJ (2021)

The covid-19 pandemic has underscored the importance of risk communication and community engagement (RCCE) in preparedness and response efforts to health threats.It has illustrated the realities of a world that is digitally interconnected, a world in which misinformation can spread more easily than ever before and contribute to the erosion of trust.Given these realities, this analysis aims to highlight the need to invest in community resilience as a core component of preparedness and response for health threats. Covid-19 in context: the first digital pandemicCommunication during disease outbreaks, particularly for novel pathogens, is challenging.Rapidly evolving statistics, health information, recommended public health measures, and best practices must be communicated consistently and transparently, and tailored for a wide variety of audiences.These audiences often have differing languages and dialects, cultural and religious beliefs, and access to information technology.
Abstract P477: A Novel <i>SMYD1</i> Variant (c.302A&gt;G) Leads To Dilated Cardiomyopathy And Biventricular Heart Failure.
Authors: Marta Szulik, Miguel Reyes-Mugica, Daniel F Marker, Lina Ghaloul-Gonzalez, Sarah Franklin
Journal: Circulation Research (2021)

The lysine methyltransferase SMYD1 was first identified in mice and shown to be important for embryonic cardiac development. Subsequently, we reported the first analysis of SMYD1 in adult myocardium and demonstrated that cardiomyocyte-specific loss of SMYD1 lead to progressive cardiac hypertrophy and heart failure, and showed that this enzyme is necessary to maintain metabolic homeostasis through transcriptional regulation of mitochondrial energetics in adult mice. While SMYD1 has been the subject of several additional studies in zebrafish and mice, since it was first identified, only in the last few years have human patients been identified with variants in the SMYD1 gene thought to be responsible for their cardiomyopathies. Specifically, two patients have been identified to date, the first patient displaying hypertrophic cardiomyopathy had a de novo heterozygous variant (c.814T&gt;C) and the second patient with left ventricular non-compaction cardiomyopathy and arrhythmias had a truncating heterozygous variant (c.675delA). Here we report a third patient with biventricular heart failure containing a homozygous variant (c.302A&gt;G; p.Asn101S) in the SMYD1 gene which was identified by a whole exome sequencing. Our histopathological analysis of cardiac tissue and skeletal muscle from the proband showed abnormalities in myofibrillar organization in both cardiac and skeletal muscle suggesting that SMYD1 is necessary for sarcomere assembly and organization. In addition, we observe markedly abnormal myocardium with extensive fibrosis and multifocal calcification, and our ultrastructural (EM) analysis revealed presence of abnormal mitochondria with reduced and irregular or lost cristae. Lastly, we have performed structural modeling of SMYD1 containing the p.Asn101Ser variant (N101S) and report how this variant may affect the enzymatic activity of SMYD1 due to its proximity to the substrate binding site. The identification of this novel variant constitutes the third patient with a SMYD1 variant displaying cardiomyopathy and provides insights into the molecular functionality of this protein. In addition, this is the first analysis of tissue from a patient expressing a SMYD1 variant which provides critical insights into the role of SMYD1 in the heart and how loss of function mutations can effect cardiac physiology.
CBIO-17. A NOVEL ROLE FOR ATR KINASE DETERMINES GLIOBLASTOMA TUMOUR CELL INVASION
Authors: ross carruthers, Sarah Derby, Karen Strathdee, Anthony Chalmers, Jim Norman, Joanna Birch
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND: Widespread contamination of the brain with malignant cells is a predominant feature of glioblastoma (GBM) and fatal brainstem infiltration is frequently observed at autopsy. Whilst radiotherapy improves survival, irradiation increases GBM cell invasion, resulting in sublethal dose to cells migrating outside the irradiated volume. Tumour cell invasion should be a therapeutic priority if survival is to be improved. The responsible molecular mechanisms are key to improving outcomes but remain enigmatic. Ataxia telangiectasia and rad3-related (ATR) is a DNA damage response (DDR) kinase involved in DNA replication stress (RS) response and is an established therapeutic target for GBM. In this study we demonstrate a novel role for ATR kinase in facilitating malignant cell invasion. METHODS AND RESULTS: Invading margins of human GBM samples demonstrated increased pATR expression relative to core. Live cell imaging demonstrated a reduction in cell velocity following ATR inhibition (ATRi; VE822) or ATR siRNA, and a retraction defect was evident in vitro. Extensive cytoplasmic vacuolation occurred following ATRi or siRNA which were single walled structures on electron microscopy which could engulf high molecular weight dextran, suggesting blockade of macropinosome processing. Live cell imaging with GFP-integrin α5 and integrin recycling assays showed integrin sequestration within macropinosomes and reduced integrin internalisation respectively. Interrogation of a published ‘ATR interactome’ revealed ATR targets with functions in endocytic vesicle trafficking. Intravital in vivo imaging of murine xenograft tumours confirmed vacuolation and dextran uptake following ATRi, whilst a further study demonstrated reduced invading tumour cells following ATRi in intracranial xenografts. CONCLUSION: We demonstrate a novel role for ATR in facilitating macropinocytic vesicle trafficking and integrin internalisation. ATRi results in a profound motility defect in vitro and in vivo. ATR inhibitors are entering early phase trials as radiation sensitisers and we propose that therapeutic benefit will extend beyond DNA damage potentiation.
Abstract 11235: Timing of Repair in Post-Infarction Ventricular Septal Defect
Authors: Rahul Jaswaney, Shilpkumar Arora, Nischay Shah, Mohammed Najeeb Osman, Yasir Abu-Omar, Mehdi H Shishehbor
Journal: Circulation (2021)

Background: Post-infarction ventricular septal defect (PIVSD) formation is a rare but devastating complication of ST-elevation myocardial infarction (STEMI). Objective: To determine the association of the timing of VSD repair on in-hospital mortality in patients with PIVSD. Methods: This retrospective cohort study identified 10,902 patients with VSD and STEMI from the Nationwide Readmissions Database from 2003-2018. VSD repair was identified by appropriate ICD9 and ICD10 codes. Patients were stratified based on intervention timing: 0-7 days, 8-14 days, and &gt; 14 days after admission. The primary outcome was in-hospital mortality. Outcomes of patients who received VSD repair were compared patients who did not receive VSD repair within the same time-point. Multivariate logistic regressions were used to adjust for demographic, comorbid, and socioeconomic factors. Analysis was stratified by clinical presentation of cardiogenic shock. Results: In patients in shock, there was a significant decrease in in-hospital mortality with VSD repair at 0-7 days (50.8% vs. 60.4%; OR 0.76; 95% CI 0.68-0.86, p&lt;0.001) as compared to at risk patients who did not undergo VSD repair (Table 1). There was no difference in in-hospital mortality in patients receiving VSD repair at 8-14 days or at &gt; 14 days as compared to who did not undergo VSD repair. In patients not in shock, there was an increase in in-hospital mortality in patients who received VSD repair from 0-7 days (23.8% vs 36%; OR 1.59; 95% CI 1.33-1.90; p&lt;0.001) at compared to those who did not receive VSD repair. There was no significant difference in outcomes in patients not in shock who received VSD repair at 8-14 days or at &gt;14 days as compared to those at who did not receive VSD repair at this timepoint. Conclusions: Early PIVSD repair was associated with a significantly decreased rate of in-hospital mortality in patients in shock, but was associated with significantly higher rate of in-hospital mortality in patients not in shock
Abstract 13400: STAT3 ASO-Loaded Microbubbles With Pulsed Ultrasound for Enhanced Therapeutic Effect in Head and Neck Tumors
Authors: Thiruganesh Ramasamy, Xucai Chen, Daniel E Johnson, Jennifer Grandis, Flordeliza S Villanueva
Journal: Circulation (2021)

Introduction: Signal transducer and activator of transcription 3 ( STAT3 ) is an oncogenic transcription factor implicated in carcinogenesis, tumor progression, and drug resistance in many cancers, including head and neck squamous cell carcinoma ( HNSCC ). STAT3 antisense oligonucleotide ( ASO ) specifically targeting the nucleotide sequence of STAT3 has therapeutic promise, but effective delivery remains challenging. We developed microbubble ( MB ) delivery vehicles loaded with STAT3 ASO and hypothesized that compared to intravenous ( i.v. ) delivery, ultrasound-targeted microbubble cavitation ( UTMC )-mediated ASO delivery confers superior tumor growth inhibition. Methods: Lipid MBs loaded with STAT3 ASO (S3MB) or mutant ASO (Mut-MB) were prepared. First, murine squamous carcinoma cells (SCC-7) in contact with MBs were exposed to pulsed ultrasound (1 MHz, 0.5 MPa, 100 μs pulse duration, 1 ms pulse interval) for 10 sec to establish efficacy with respect to cytotoxicity, apoptosis, and gene knockdown. Thereafter, the anti-tumor effect of 3 treatments with STAT3 ASO (10 μg) delivered i.v. or via UTMC x 15 min ( f= 1MHz, 0.7MPa, 100 cycles x 5 every 2 sec) was compared in vivo in a murine SCC-7 xenograft model followed up to 17 days. Results: S3MB + UTMC conferred more cytoxocitiy, apoptosis, and downregulation of transcripts for STAT3 and its target genes (Bcl-xL and Cyclin D1) compared to Mut-MB + UTMC in vitro (p&lt;0.05). In tumor bearing mice, compared to i.v. STAT3 ASO (n=8), Mut-MB+UTMC (n=5) or no treatment (n=8), S3MB + UTMC (n=9) significantly attenuated tumor burden, prolonged doubling time, and improved survival (p&lt;0.05). While i.v. STAT3 ASO had no effect on tumor expression of STAT3, Bcl-x, and cyclin D1 at the transcript and protein levels, its delivery via UTMC significantly reduced tumor expression of these genes (p&lt;0.01). Conclusion: At a dose of 10 μg, STAT3 ASO significantly inhibited murine HNSCC tumor growth and downregulated STAT3 and its target genes when delivered via UTMC, compared with intravenous administration alone. Our platform offers a promising imaged-guided, targeted delivery strategy for nucleotide-based therapeutics in cancer applications.
Abstract 12159: Impact of Ischemic Heart Disease on Cardiac Resynchronization Therapy - Analysis From National Inpatient Sample
Authors: Steve Balian, Steve Balian, Waqas Khan, Jawad Hassan, Abdul Minhas, Beth Bailey, Zulfiqar Qutrio Baloch, Sandeep Banga, george Abela
Journal: Circulation (2021)

Introduction: Comparative outcomes of hospitalizations for Cardiac Resynchronization Therapy (CRT) implantation procedures with and without coexisting Ischemic Heart Diseases (IHD) have not been studied at national level databases. We attempted to assess outcomes and baseline characteristics in these hospitalizations based on the National Inpatient Sample (NIS). Hypothesis: Ischemic heart disease worsens inpatient outcomes in patients undergoing CRT implantation. Methods: We conducted a retrospective analysis of hospitalizations for CRT implantation from the National Inpatient Sample (NIS) between 2013 and 2014. ICD-9 Billing codes were used to identify the target population. The primary outcomes were inpatient mortality, and hospital length and cost of stay. Results: A total of 11057 cases were identified. IHD was listed as any diagnosis in 66% of these hospitalizations. The mean age was 72.5 and 66.9 years for CRT implantation with and without IHD, respectively. Hospitalizations without IHD were more likely to be female (44% vs. 25%; p=0.01). Patients in the CRT with IHD group had a higher comorbidity burden with a higher proportion of hypertension, chronic kidney disease, anemia, peripheral artery disease, and congestive heart failure (Table 1). Inpatient mortality was similar between both groups (OR 1.17, CI 0.75-1.81). The IHD cohort had higher rates of cardiac arrest (OR 1.30, CI 1.05-1.62), acute kidney injury (OR 1.21, CI 1.08-1.35), longer length and a higher cost of stay (Table 1). Conclusions: IHD is associated with higher costs, longer length of stay, and higher rates of cardiac arrest. However, the in-hospital mortality was not different between the two groups. Higher incidence of cardiac arrest in patients with CRT and IHD underlines the importance of ICD with CRT. The clinical implication is that the threshold of selecting a CRT-D device in patients eligible for CRT therapy should be lower in patients with IHD vis-à-vis patients without IHD.
Abstract 12242: Nanoporous Microgel Encapsulation of Extracellular Vesicles Enhances Lung Delivery for the Treatment of Pulmonary Vascular Diseases
Authors: Nicholas D Cober, Yupu Deng, Katelynn Rowe, Ainara Benavente-Babace, David W Courtman, Michel Godin, Duncan J Stewart
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a devastating lung disease with no curative treatments available. Cell-based therapies are a promising regenerative approach, including the direct application of stem cell derived extracellular vesicles (EVs). Mesenchymal stromal cells (MSCs) have shown promise as a treatment for many cardiovascular diseases; their therapeutic effects are predominately mediated by paracrine mechanisms, in particular the release of EVs. Yet, systemically administered EVs are rapidly cleared to the liver and spleen, with minimal lung accumulation. Hypothesis: We hypothesized that encapsulation of EVs within nanoporous microgels would provide a novel therapeutic product to improve EV lung delivery and retention and therefore enhance their therapeutic benefits. Methods &amp; Results: MSC-derived EVs were purified using tangential flow filtration resulting in a median size of 108±53nm by nanoparticle tracking analysis, and positive for CD63 by Western blot. EV-loaded microgels were prepared using a microfluidic device producing agarose-gelatin (1%-1%) microgels of 47.2±0.4um diameter. In vitro uptake assays were performed with DiR or pkh26 labelled EVs and quantified by microscopy. Encapsulated EVs demonstrated a delayed-release profile in vitro with reduced HUVEC uptake over 24h (9.7±1.1% encap. vs. 46±5.3% free). In vivo biodistribution studies were performed in the monocrotaline model of PAH using central intravenous delivery. EV-loaded microgels were efficiently retained within the lungs after 24h (81±12% encap vs. 7.5±0.4% free), while free EVs accumulated in the liver (74±2.3% free vs 10±2.5% encap). Furthermore, lung digestion and flow cytometry analysis revealed that encapsulated EVs were readily taken up by CD45+ immune cells and CD31+ endothelial cells to a greater extent than free EVs, indicating enhanced interaction with the local lung microenvironment. Conclusion: Microencapsulation of EVs results in significantly enhanced local retention within the lung, leading to increased local cellular uptake compared to systemically administered EVs.
Abstract 10944: A Network Analysis to Identify Pathophysiological Pathways Associated with Systolic Function Recovery After Myocardial Infarction
Authors: Peter Wohlfahrt, Vojtech Melenovsky, Vendula Novosadova, Dominik Jenca, Jolana Mrazkova, Marek Sramko, Michael Zelizko, Martin Kotrc, Ashkan Zareie, Carlos E Trufen, Jan Pitha, Vera Adamkova, Josef Kautzner, Petr Jarolim
Journal: Circulation (2021)

Introduction: Identification of factors involved in early stages of left ventricular systolic function recovery after acute myocardial infarction (AMI) can provide a basis for novel therapies. We aimed to characterize proteomic biomarkers and underlying mechanistic pathways associated with improvement of left ventricular systolic function. Hypothesis: Proteomic biomarkers and protein-protein interaction pathways differ between patients with and without systolic function recovery after AMI. Methods: Patients with ejection fraction (EF) &lt;40% at hospital discharge were selected from a prospective registry of AMI patients (n=819). We used matched case-control design. Cases were patients with EF&lt;40% at hospital discharge, but EF&gt;50% at the follow-up visit 3-6 months after discharge (EF recovery group). Controls were patients with EF&lt;40% both at hospital discharge and follow-up visit. Controls were matched for age, gender, and discharge EF. Blood samples were drawn within 24h since hospital admission. We used proximity extension assays (Olink, Uppsala) to measure plasma biomarkers and protein-protein interaction network to identify pathophysiological pathways distinguishing cases and controls. Results: In total, 41 cases and 41 controls (mean age 59±10 years, 73% males) were included. At baseline, study groups did not differ in the main clinical variables. Of the 362 biomarkers tested, and after adjustment for age, gender and baseline EF, 44 proteins were differentially expressed, of which 2 (interleukin 6 and stem cell factor) showed association with EF recovery after false discovery rate correction. In the Reactome pathway analysis, Interleukin-6 family signaling was the most significant pathway associated with systolic function recovery. Conclusions: We identified the Interleukin-6 family signaling pathway with IL-6 and leukemia inhibitory factor (LIF) as potential early factors supporting recovery of systolic function after AMI.