tbuckley/cabot-search huggingface dataset:
Abstract MP246: Epigenetic Regulation At <i>LRP1</i> Susceptibility Locus And Characterization Of <i>LRP1</i> Function In Human Induced Pluripotent Stem Cells Derived Smooth Muscle Cells
Authors: LU LIU, Adrien Georges, Nabila Bouatia-Naji
Journal: Circulation Research (2021)

Introduction: The low-density lipoprotein receptor-related protein 1 (LRP1), an endocytic receptor highly expressed in smooth muscle cells (SMCs), participates in diverse biological processes. A common genetic variant located in LRP1 first intron, rs11172113, was associated with several vascular diseases, including coronary artery disease, migraine and spontaneous coronary artery dissection, as well asd with LRP1 expression in arterial tissues. However, the biological mechanisms through which rs11172113 influence LRP1 function in the context of arterial lesions is not fully understood. Methods: We applied in silico functional annotation to select variants and measured their enhancer activity using luciferase reporter assay in rat primary cells (A7r5). We performed siRNA knockdown of LRP1 and 4 transcription factors (TFs) predicted to interact with rs11172113 in human induced pluripotent stem cells (iPSCs) derived SMCs. We analyzed both contractile (CSMCs) and synthetic (SSMCs) differentiated cells. We edited iPSCs prior to differentiation using CRISPR-Cas9 to generate 100 bp deletion of the enhancer region containing rs11172113. We also created frame-shift indels in exons 2 or 5 of LRP1 in iPSCs to create SMCs knockouts. Results: Seven variants in LRP1 locus co-located with enhancer (histone marks) and open chromatin regions (ATAC-Seq peaks) in SMCs and arterial tissues. Reporter assay in rat SMCs confirmed that rs11172113 belongs to a genomic region showing enhancer activity in vitro . iPSCs with homozygous deletion of rs11172113 enhancer region presented the same pluripotency compared with wild type, and iPSC derived SMCs showed positive expression of specific markers for each phenotype. We found that the deletion of enhancer region decreased the expression of LRP1 in both CSMCs and SSMCs. LRP1 knockdown decreased SSMCs and CSMCs proliferation capacity, but increased cell migration. Knockdown of TFs and iPSCs derived CSMCs and SSMCs with LRP1 knockout are currently under assessment. Conclusions: We confirmed rs11172113 to regulate LRP1 expression in iPSCs derived synthetic and contractile SMCs. Our results support LRP1 effect on SMCs phenotype alteration as a potential mechanism in genetic susceptibility for vascular disease.
Abstract 12636: ECG-Based Risk Stratification of Long-Term Mortality in Suspected Acute Coronary Syndrome
Authors: Zeineb Bouzid, Ziad Faramand, Stephanie Frisch, Richard Gregg, Ervin Sejdic, Salah S Al-Zaiti
Journal: Circulation (2021)

Introduction: Non-invasive risk stratification can play a significant role in the initial triage of patients with suspected acute coronary syndrome. Numerous ECG features have been previously linked with mortality in both the general and cardiac populations. We sought to build an ECG-based model that can predict time-to-death in high-risk chest pain patients transported by Emergency Medical Services. Methods: This was a prospective observational cohort study of patients evaluated for suspected acute coronary syndrome. The study recruited consecutive patients evaluated at the emergency department of three UPMC-affiliated tertiary care hospitals. We included consecutive patients in whom a prehospital echocardiogram was performed during indexed encounter. Baseline ECGs were preprocessed using manufacturer specific algorithms. We evaluated 554 temporal-spatial features of the 12-lead ECG in multivariate proportional hazards Cox regression model for predicting all-cause death during long term follow up. Death was ascertained using phenotyping UPMC electronic hospital records and through the CDC National Death Index database. Model fit was evaluated using C-statistic and AIC. We set alpha at 0.01 for two-tailed hypothesis testing. Results: Our sample included 2311 patients (aged 59 ± 16.6, 47% females, 41% Black). Over a median follow up period of 1868 days (IQR = 688; [Q1, Q3] = [1511, 2199]), there was 622 (26.9%) adjudicated deaths. During univariate analysis, 288 features were significantly associated with time-to-death. In the final multivariate model (c-statistic = 0.79, AIC = 9066.05), controlling for demographic and clinical data, 15 ECG features remained predictive of the study outcome, with Selvester score being the strongest predictor (Hazard Ratio = 1.09, 95% CI = 1.03 - 1.16). Other clinically important ECG features included horizontal-plane QRS axis, QRS-T angle, QTc interval, QTpeak, T peak-end, S wave morphology the inferior leads, QRS morphology in lead aVR, and T wave morphology in the anterior leads. Conclusions: The presenting 12-lead ECG can serve as a powerful risk stratification tool of long-term mortality in patients with chest pain. Selvester score can serve as a plausible and easy to use clinical decision tool.
Abstract 11910: Prevalence and Variation in Malnutrition in Non-Obstructive Coronary Artery Disease
Authors: Brandon H Schwartz, Nare Torosyan, Billy Chen, Joseph E Ebinger, Heidi Gransar, Daniel Berman, C N Bairey Merz
Journal: Circulation (2021)

Introduction: Prior work demonstrates up to 50% of patients with acute coronary syndrome are malnourished, as evaluated by the Controlling Nutritional Status (CONUT) score. We investigated the prevalence of malnutrition in stable nonobstructive coronary artery disease (CAD) detected by coronary computed tomography angiography (CCTA) versus invasive coronary angiography (ICA). Methods: In a single-center, retrospective cohort, we examined the electronic health records of 429 patients with normal coronary arteries (NCA) without evidence of atherosclerosis on CCTA (n=144), nonobstructive CAD (&lt;70% stenosis) by CCTA (n=143), or ICA (n=142) on clinically ordered studies for chest pain or exertional dyspnea. CONUT scores, an aggregate of albumin, lymphocyte count, and total cholesterol, were calculated at time of CCTA or ICA in patients with available lab values. Patients within each group were stratified by severity of malnutrition defined as none (0-1), mild (2-4), moderate (5-7), or severe (8-12). Diabetic patients were excluded. Number of risk factors including history of hypertension, hyperlipidemia, or smoking were compared. Results: Among all patients with complete data (n=332), 33% overall had malnutrition, including 31% with mild, 2% with moderate, and none with severe malnutrition. In patients with NCA, 24% had malnutrition, compared to 31% in nonobstructive CAD by CCTA and 45% in ICA. There was a direct positive relationship between malnutrition presence and severity with age, cardiac risk factors and the presence of nonobstructive CAD ( Table ). Conclusions: Malnutrition is present in over one-third of stable patients with no obstructive CAD and directly associated with age, risk factor burden, and nonobstructive CAD. Future prospective studies are needed to understand whether malnutrition directly contributes to development of CAD or if age and cardiac risk factors associated with CAD lead to progression of malnutrition, or both.
INNV-23. CASE REPORT OF CISPLATIN + ETOPOSIDE FOR THE TREATMENT OF METASTATIC MALIGNANT MENINGIOMA
Authors: Minhdan Nguyen, Judy Truong, Akanksha Sharma, Santosh Kesari, Jose Carrillo, Jared Chow, Eve Landa, Chester Griffiths, Daniel Kelly, Naveed Wagle
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Meningioma have an annual incidence of 5 per 100,000 and is the most frequent primary tumor of the central nervous system. Risk factors include radiotherapy and hormone intake. Most meningioma are grade I benign tumors, but up to 15% are atypical and 2% anaplastic according to the WHO 2016 histological criteria. Extra-CNS metastasis is exceedingly rare but carry a poor prognosis. Surgical resection and radiation therapy are the only approved therapies for the treatment of high grade or recurrent meningioma. Chemotherapy options have been limited and none have shown significant response rates. METHODS We report a case of a 33 year old male with an anaplastic meningioma (WHO Grade III) with metastasis to the lungs and rapid progression despite repeat resection. The subject was previously treated with resection and radiation therapy to a skull base/sinonasal lesion. Progression occurred at anterior cranial fossa, which required repeat resection. Within a month, the meningioma showed substantial progression with invasion into the orbit and nasopharynx as well as metastasis to the lung. The subject experienced significant clinical decline which included bilateral vision loss. The subject was treated with Cisplatin and Etoposide for 4 cycles. RESULTS The patient had immediate clinical improvement after the first cycle. Repeat MRI imaging of the brain showed partial response with approximately 40% tumor reduction, and CT of the chest showed complete response. The subject’s performance status also improved significantly with treatment including recovery of eyesight bilaterally. CONCLUSION This case showed that the use of Cisplatin + Etoposide for metastatic malignant meningioma can have significant objective and clinical response. The use of this regimen warrants further investigation. A clinical trial is currently being developed.
Abstract 12307: Differences in Outcomes Between Men and Women Enrolled in Chronic Disease Programs for Diabetes, Hypertension and Hyperlipidemia
Authors: Lisa Norsen, Elizabeth Anson, Holly Lavigne, Ging Hoang, Irena Pesis-Katz, Renu Singh
Journal: Circulation (2021)

Ischemic heart disease (IHD) affects over 48 million women in the US and is the leading cause of death. Hypertension, diabetes and dyslipidemia are risk factors for the genesis of IHD in women. Disease management programs (DM) have proven effective, overall, in facilitating lifestyle change and adherence to treatment plan but little is known about the effectiveness of these programs for men versus women. The purpose of this program evaluation was to identify differences in outcomes between men and women who participated in DM programs for hypertension, diabetes and dyslipidemia.Between 2015 and 2019, 616 unique individuals completed one of these DM programs. Measures of height, weight, exercise minutes, sedentary lifestyle, healthy nutrition, sleep, hydration and medication adherence were taken at the first and last visit. The sample was primarily female (70%), white (76%), Married (67%), educated (93% had bachelor’s or better), and were 49.3 years old, on average. Analysis revealed that males and females differ in response to the DM programs. While there was significant decrease in BMI for all participants (p&lt;.001), the decrease was significantly greater for males compared to females (-0.60 vs. -0.29, respectively, p&lt;.01). While exercise minutes did not differ between males and females from pre to post measurement, males who had zero exercise minutes at pre-test increased exercise minutes post program by a significantly greater amount than females who were not exercising at pretest (p=.02). Decreases in the number of missed medication days were significantly greater for women than men (0.50 days vs. 0.17 respectively; p=.02). Interestingly, while males did decrease significantly (p=.02), the decrease in medication days missed were far more substantial for females (p&lt;.001).Men and women differ in their response to DM programs focused on lifestyle modification. Interventions should be individualized based on sex and designed specifically for women in order to optimize outcomes.
Community–academic partnerships addressing local health inequalities during COVID-19: a qualitative evaluation
Authors: Meerat Kaur, Bethany Golding, Arti Maini, Sonia Kumar
Journal: The Lancet (2021)

BackgroundDuring the COVID-19 pandemic, inequalities among communities were amplified and local organisations had reductions in resources. In response, seven community organisations, an academic primary care and public health department, and 25 medical students partnered to co-create tailored projects to address community-defined goals. We aimed to explore community perspectives from such a partnership approach.MethodsWe did a qualitative realist evaluation to explore what works, why, and for whom regarding the community–academic partnerships. Data were gathered through ten semistructured interviews and one focus group. Themes were constructed from iterative deductive and inductive coding conducted in NVivo 10. These themes were used to continually test and refine propositions co-created with the community partners that hypothesised key components of successful partnerships that could provide a useful response during a pandemic.FindingsBetween June 9 and Aug 20, 2020, we gathered data from 12 community partners (nine women and three men). The community–academic partnerships led to co-creation of tangible outputs that responded to challenges facing communities experiencing poor health outcomes pre-pandemic. Enablers of effective partnerships included developing faculty–community relationships, articulating common goals tailored around local priorities, recognition of community value, and adopting a flexible, collaborative process throughout. Short timelines and long quality assurance processes were perceived as barriers. Longstanding inequalities impeded the ability of outputs to address needs for certain communities. For example, a video about COVID-19 was produced in multiple languages but not translated into Somali quickly enough, despite the absence of appropriate communications for this community. The medical students were perceived by community partners to add capacity and technical expertise. An example output was a co-produced resource pack for low-income, single parent families, accompanied by a public health campaign encouraging participation in healthy, creative activities.InterpretationThe findings highlighted the enablers and barriers to successful community–academic partnerships that achieved their goals, as defined by the community. Community-academic partnerships have the potential to offer increased capacity for community interventions as a response to the COVID-19 pandemic through student involvement.FundingWest London Health Partnership funded two of the projects mentioned in the Abstract. This abstract presents independent work commissioned by the National Institute for Health Research (NIHR) under the Applied Health Research programme for North West London. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
Abstract 14362: Retention of CD34+ Progenitor Cells in the Coronary Circulation Correlates With Insulin Levels Depending on Insulin Resistance
Authors: Ilke Ozcan, Takumi Toya, Ali Ahmad, Valentina Nardi, Nazanin Rajai, Lilach Lerman, Amir Lerman
Journal: Circulation (2021)

Introduction: Diabetes mellitus and insulin resistance are associated with accelerated vascular injury and progression of coronary atherosclerosis. CD34 + progenitor cells are mobilized and recruited to repair the endothelial and vascular damage. Hypothesis: We hypothesized that the interaction of insulin levels and retention of CD34+ progenitors in the coronary arteries will be different between patients with and without insulin resistance. Methods: In patients with no obstructive coronary artery disease (NOCAD: &lt;40% angiographic stenosis), blood samples were collected concurrently from the proximal aorta and the coronary sinus, and CD34+ cells counted using flow cytometry. CD34+ cells gradient was calculated by subtracting aortic from coronary sinus cell counts, with a higher gradient reflecting lower retention. Patients on antidiabetic medications were excluded. Insulin resistance (IR) was estimated as HOMA-IR index ([insulin]*[glucose]/405)) ≥2. Results: Of 128 patients (mean age 51±11 years, 77% females), 60 (47%) had IR (mean age 51±10 years, 73% females) and 68 (53%) did not (mean age 50±13 years, 79% females). The groups did not differ in age, sex or LDL cholesterol. The IR group had higher BMI and triglyceride levels and lower HDL cholesterol. CD34 + cell gradient correlated directly significantly with insulin levels in patients without IR (r=0.25, p=0.04) (Fig1A) , but inversely in those with IR (r=-0.39, p=0.01) (Fig1B) . Both associations remained significant after adjustment for age, sex, and BMI (IR: r=-0.39, p=0.02; no IR: r=29, p=0.04). Conclusions: In NOCAD patients with IR, higher levels of serum insulin were associated with increased retention of CD34 + cells in the coronary arteries. The current study supports a potential role for CD34 + cells for vascular repair in patients with IR.
Abstract 12116: Sex Differences in Arrhythmia Prevalence in a Large Patient Cohort Examined With Mobile Cardiac Telemetry
Authors: Linda S Johnson, Marek J Dziubinski, Natan Napiorkowski, Olga Witkowska, Agnieszka Grotek, Magdalena E Slusarczyk, Andrea M Russo
Journal: Circulation (2021)

Introduction: The frequency of clinically relevant arrhythmia on long-term ambulatory ECG recordings is not sufficiently well described. We aimed to address this in a large patient cohort monitored with mobile cardiac telemetry. Methods: All patients 18-100 years who were monitored in the USA in 2017 (n=27.203, 58% female) with the PocketECG device (MediLynx), which registers and transmits a full-disclosure ECG for ≤30 days with beat-to-beat analysis, were included. Frequent premature ventricular complexes (PVCs) and frequent premature atrial complexes (PACs) were defined as ≥200 PVCs or ≥500 PACs in any recording day. Supraventricular tachycardia (SVT) episodes were defined as both any SVT &gt;3 beats, and SVT ≥30 seconds. AV-blocks II and III were not differentiated. Results: In the 18-40-year age group the overall prevalence of any arrhythmia was low (Figure 1 a-f). Frequent PACs, atrial fibrillation, AV-blocks and ventricular arrhythmias were more common in men than women (all p&lt;0.0001), and SVTs, both &gt;3 beats and &gt;30 seconds, were more common in women (p&lt;0.001 and p&lt;0.004, respectively). The overall prevalence of any VT event was 22.9% in women and 40.8% in men (p&lt;0.0001) and the mean age at onset of VT was lower in women (71.9 vs 72.6 years, 95%CI for difference (-1.3; -0.3). Conclusions: Most arrhythmias are more prevalent among men of all ages, but SVTs are more prevalent among women. VT events are common in a patient population, and the age at onset of ventricular tachycardia is lower among women.
Intratumoral co-injection of the poly I:C-derivative BO-112 and a STING agonist synergize to achieve local and distant anti-tumor efficacy
Authors: Maite Alvarez, Carmen Molina, Carlos E De Andrea, Myriam Fernandez-Sendin, Maria Villalba, Jose Gonzalez-Gomariz, Maria Carmen Ochoa, Alvaro Teijeira, Javier Glez-Vaz, Fernando Aranda, Miguel F Sanmamed, Maria E Rodriguez-Ruiz, Xinyi Fan, Wen H Shen, Pedro Berraondo, Marisol Quintero, Ignacio Melero
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid that acting on toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5) and protein kinase RNA-activated (PKR) elicits rejection of directly injected transplanted tumors, but has only modest efficacy against distant untreated tumors. Its clinical activity has also been documented in early phase clinical trials. The 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulator of interferon genes (STING) agonist shows a comparable pattern of efficacy when used via intratumoral injections. Methods Mice subcutaneously engrafted with bilateral MC38 and B16.OVA-derived tumors were treated with proinflammatory immunotherapy agents known to be active when intratumorally delivered. The combination of BO-112 and DMXAA was chosen given its excellent efficacy and the requirements for antitumor effects were studied on selective depletion of immune cell types and in gene-modified mouse strains lacking basic leucine zipper ATF-like transcription factor 3 (BATF3), interferon-α/β receptor (IFNAR) or STING. Spatial requirements for the injections were studied in mice bearing three tumor lesions. Results BO-112 and DMXAA when co-injected in one of the lesions of mice bearing concomitant bilateral tumors frequently achieved complete local and distant antitumor efficacy. Synergistic effects were contingent on CD8 T cell lymphocytes and dependent on conventional type 1 dendritic cells, responsiveness to type I interferon (IFN) and STING function in the tumor-bearing host. Efficacy was preserved even if BO-112 and DMXAA were injected in separate lesions in a manner able to control another untreated third-party tumor. Efficacy could be further enhanced on concurrent PD-1 blockade. Conclusion Clinically feasible co-injections of BO-112 and a STING agonist attain synergistic efficacy able to eradicate distant untreated tumor lesions.
Abstract 14092: Arachidonate 5 Lipoxygenase Deficiency Drives Age-Related Obesity, Macrophage Dysfunction in Cardiac Repair, and Omnipresence of Inflammation
Authors: Vasundhara Kain, Ganesh V Halade
Journal: Circulation (2021)

Introduction: Age-related inflammation is the primary hallmark of heart failure with reduced and preserved ejection fraction; however, the fundamental source of inflammation is unclear. Arachidonate 5 lipoxygenase (ALOX5) is known to direct the biosynthesis of leukotrienes and proinflammatory mediators (PIMs) that orchestrate the initiation of inflammation following myocardial infarction (MI). Hypothesis: Thus, we set out to test the role of ALOX5 to understand inflammation-resolution signaling in acute HF in aging. Methods: Male C57Bl/6J and ALOX5 -/- mice were divided into two groups: 1) young (2-4 months) and 2) aging (18 months). Mice were subjected to MI surgery that develops acute heart failure maintaining no-MI as naïve controls. Cellular and molecular mechanisms are detemined. Results: The absence of ALOX5 leads to age-related obesity with series of metabolic defects, including fatty liver. Next-gen sequencing analysis revealed that immune regulating pathways of infarcted myocardium were dysregulated in young and aging ALOX5 -/- mice compared to respective age-matched controls. In response to cardiac injury, ALOX5 -/- mice fail to initiate an inflammatory response with reduced leukotrienes B 4 and PIMs, with marked obesity-related chronic inflammation in immune defense hubs: spleen bone marrow and LV infarcted site. At the molecular level, ALOX5 deletion also reduced resolution mediators (specialized proresolving mediators; SPMs), thereby making macrophage dysfunctional with the decrease in SIRP-α. Aging superimposed on ALOX5 deficiency triggers macrophage dysfunction with the increase in proinflammatory phenotype (Ly6C hi ) and notable upregulation of CXCR4 and downregulation of resolution receptor formyl peptide receptor 2; in infarcted heart post-MI. Conclusions: Presented age-related outcome provides translational insight that ALOX5 serves as a connector for initiating PIM (turn-on) and SPMs (turn-off) essential for macrophage function and cardiac repair processes. Thus, future research is warranted to validate the role of ALOX5 in cardiometabolic defects, PIMs, and resolution mediators (SPMs) in heart failure with reduced and preserved ejection fraction.