tbuckley/cabot-search huggingface dataset:
Abstract 10587: Frequency and Outcomes of Bradyarrhythmias in the Community
Authors: Julian Haimovich, Shaan Khurshid, Paolo Di Achille, Victor Nauffal, Pulkit Singh, Christopher Reeder, Lia Harrington, Xin Wang, Gopal Sarma, Jelena Kornej, Emelia J Benjamin, Anthony A Philippakis, Puneet Batra, Patrick T Ellinor, Steven A Lubitz
Journal: Circulation (2021)

Introduction: Bradyarrhythmias, diseases characterized by slow heart rates, are associated with substantial morbidity. Contemporary estimates of the frequency of bradyarrhythmias and associated outcomes in the community are needed. Methods: We examined the prevalence and incidence of bradyarrhythmias in a multi-institutional electronic health record cohort comprised of individuals receiving primary care. We used an automated tool to ascertain diagnoses from 12-lead electrocardiogram (ECG) diagnostic statements. We defined bradyarrhythmia groups based on location and severity of disease. We tested associations between clinical risk factors and incident bradyarrhythmia groups using multivariable proportional hazards regression. To characterize potential associations between bradyarrhythmias and major adverse cardiovascular events (MACE, a composite of myocardial infarction, heart failure, stroke, and death), we matched incident bradyarrhythmia and non-bradyarrhythmia individuals 1:1 on age, sex, and duration of preceding follow-up, and included bradyarrhythmia exposure in multivariable regression with MACE as the outcome. Results: Of a total of 520,868 individuals (mean age 48, 62% female, 3.5 million ECGs), the prevalence of any bradyarrhythmia was 10%. After excluding individuals with prevalent bradyarrhythmia, a total of 49,513 events occurred in 440,370 individuals as shown in Figure 1. Bradyarrhythmias were associated with common modifiable cardiovascular risk such as diabetes (HR 1.26, 95% CI [1.22-1.29]) and hypertension (HR 1.24, 95% CI [1.22-1.27]). Bradyarrhythmias were significantly associated with MACE in the atrioventricular delay (HR 1.07, 95% CI [1.01-1.14]) and conduction delay groups (HR 1.19, 95% CI [1.13-1.25]). Conclusions: Bradyarrhythmias are common and increase with older age and male sex. Incident bradyarrhythmias are associated with cardiovascular risk factors and may be associated with MACE.
CBIO-04. G-QUADRUPLEX STABILIZATION ENHANCES REPLICATION STRESS AND DNA DAMAGE IN ATRX-DEFICIENT HIGH-GRADE GLIOMA
Authors: Sharvari Dharmaiah, Vasudev Tadimeti, Prit Benny Malgulwar, Christian Alvarez, Ahsan Farooqi, Jason Huse
Journal: Neuro-Oncology (2021)

Abstract Loss of function mutations in α-thalassaemia/mental retardation X-linked (ATRX) are a critical molecular hallmark for invariably fatal high-grade glioma (HGG). Mutational inactivation of histone chaperone ATRX leads to accumulations of abnormal DNA secondary structures known as G-quadruplexes (G4s), thereby inducing replication stress and DNA damage. As G4s arise at GC-rich regions (i.e., pericentromeric and telomeric regions), ATRX-deficiency alters genome-wide accessibility of chromatin, leads to transcriptional dysregulation, and induces alternative lengthening of telomeres (ALT). Our goal is to target ATRX deficiency through G4 stabilizers, which represent a class of novel small molecule compounds that selectively bind to and stabilize G4 structures. However, the genomic consequences and efficacy of this therapy for ATRX-deficient HGG are poorly understood. We therefore sought to evaluate the molecular mechanisms that drive selective lethality in patient-derived ATRX-deficient glioma stem cells (GSCs), following G4 stabilization. We found that ATRX-deficient GSCs demonstrate dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact controls. Cell viability assays confirmed the specificity of our G4 stabilizer in comparison to other commonly used G4 stabilizers. Interestingly, G4 stabilization activated p53-independent apoptosis in ATRX-deficient GSCs. Furthermore, ATRX-deficient GSCs exhibit upregulated expression of both ATR and ATM pathways upon G4 stabilization, indicating enhanced replication stress and DNA damage via double-stranded breaks, respectively. Our preliminary findings suggest that ATR and ATM activation leads to the inhibition of transcription factor NF-κB, which in turn drives apoptosis. Lastly, our data indicate that G4 stabilization perturbs the ALT phenotype in ATRX-deficient GSCs, likely contributing to telomeric dysfunction. Taken together, these findings suggest that G4 stabilizers could synergize with ionizing radiation, the standard of care, as they are both DNA-damaging therapies. Our work defines mechanisms of action and efficacy of a novel therapeutic strategy for ATRX-deficient HGG, with strong implications for other ATRX-deficient cancers.
Abstract 12668: Mutant Smooth Muscle α-Actin Predisposes to Atherosclerosis and Augments Cholesterol-Driven Phenotypic Modulation of Vascular Smooth Muscle Cells
Authors: Kaveeta Kaw, Abhijnan Chattopadhyay, Jiyuan Chen, Xue Yan Duan, Shuangtao Ma, Callie Kwartler, Dianna M Milewicz
Journal: Circulation (2021)

Heterozygous variants in ACTA2 (smooth muscle α-actin) predispose to thoracic aortic disease and early-onset coronary artery disease (CAD). Single cell RNA sequencing (scRNA-Seq) identified phenotypically modulated SMCs (mSMCs; de-differentiated SMCs with upregulation of macrophage and fibroblast markers) that appear with atherosclerotic plaque formation in the aortas of Apoe -/- mice. Importantly, this transition is dependent on Kruppel-like factor 4 (Klf4). We previously demonstrated that SMCs exposed to free cholesterol complexed to methyl-β-cyclodextrin (MBD-Chol) in vitro activate unfolded protein response (UPR) pathways upstream of Klf4 and assume a mSMC phenotype. Blocking the UPR Perk pathway abolishes modulation. We sought to determine how ACTA2 p.Arg149Cys causes early-onset CAD. Acta2 R149C/+ mice were generated using CRISPR/Cas9. Acta2 R149C/+ mice were crossed into Apoe -/- mice and fed a high fat diet for 3 months. Oil Red O staining and en face aortic analysis showed that Acta2 R149C/+ Apoe -/- aortas developed significantly more plaques than similarly treated Apoe -/- mice (p&lt;0.01) with no difference in plasma lipid levels ( Fig. 1A ). ScRNA-Seq of the root and ascending aorta showed no novel SMC cluster, however mSMC clusters demonstrated increased expression of UPR markers and Klf4 in the Acta2 R149C/+ Apoe -/- aortas compared to Apoe -/- aortas. Strikingly, Acta2 R149C/+ SMCs upregulate modulation markers at much lower levels of cholesterol than WT SMCs due to activation of the UPR Perk-Klf4 by misfolded mutant SM α-actin ( Fig. 1B ). Importantly, blocking Perk abolishes the augmented phenotypic modulation in Acta2 R149C/+ SMCs. These findings identify a novel pathway driving atherosclerosis independent of lipid metabolism and confirm a key role of SMCs in atherosclerotic plaque formation.
New Systemic Treatment Options for Hepatobiliary Cancers
Authors: Robin Kate Kelley
Journal: Journal of the National Comprehensive Cancer Network (2021)

Multiple systemic therapy options now exist for unresectable and metastatic hepatocellular carcinoma (HCC). Atezolizumab + bevacizumab is the preferred first-line regimen, and although many second-line treatment options have recently been added to the NCCN Guidelines, none have been studied after atezolizumab + bevacizumab (all post-sorafenib), and therefore optimal sequence has yet to be established. Multiple new combination regimens with immune checkpoint inhibitors are also being studied in advanced-stage HCC. In biliary tract cancer (BTC), gemcitabine + cisplatin remains the preferred first-line regimen. FOLFOX is the preferred regimen in the second line. Multiple targeted therapy options are now available in second-line BTC for patients with tumors harboring specific mutations, and these therapeutic targets may guide future treatment sequence and combinations for BTCs.
A phase 2 dose‐finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis
Authors: Cihan Yurdaydin, Onur Keskin, Esra Yurdcu, Aysun Çalişkan, Soner Önem, Fatih Karakaya, Çağdaş Kalkan, Ersin Karatayli, Senem Karatayli, Ingrid Choong, David Apelian, Christopher Koh, Theo Heller, Ramazan Idilman, A. Mithat Bozdayi, Jeffrey S. Glenn
Journal: Hepatology (2021)

Proof-of-concept studies demonstrated lonafarnib (LNF), a first-in-class oral prenylation inhibitor, efficacy in patients infected with HDV. The lonafarnib with ritonavir for HDV-2 (LOWR-2) study's aim was to identify optimal combination regimens of LNF + ritonavir (RTV) ± pegylated interferon alpha (PEG-IFNα) with efficacy and tolerability for longer-term dosing. Here we report the safety and efficacy at end of treatment for up to 24 weeks.
Abstract 10069: Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Left Ventricular Structure and Function in Duchenne Muscular Dystrophy Carriers
Authors: Hannah Lehrenbaum, Rahul Sheth, Daniel Cheeran, Faris Araj, Alpesh Amin, Ronald M Peshock, Mark H Drazner, Pradeep P Mammen
Journal: Circulation (2021)

Introduction: Duchenne muscular dystrophy (DMD) is a rare X-linked neuromuscular disorder affecting 1:5,000 males that results in terminal injury to the skeletal muscle and the heart. Recent evidence suggests that DMD female carriers are also at increased risk of developing cardiomyopathy. Renin-angiotensin-aldosterone system (RAAS) antagonists reduce morbidity and mortality and inhibit adverse left ventricular remodeling in patients with heart failure with reduced ejection fraction. The benefit of RAAS inhibition in DMD carriers has not been studied to date. Hypothesis: We hypothesize that RAAS inhibition will improve left ventricular function and induce favorable left ventricular structural changes in DMD carriers over time. Methods: A retrospective, single-center cohort study was undertaken to compare cardiac magnetic resonance imaging (cMRI) parameters in DMD carriers at the time of RAAS inhibitor initiation and after treatment with RAAS inhibitors for at least 12 months. RAAS inhibitors included angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor neprilysin inhibitors. Through EMR review, demographic data and cMRI parameters were collected retrospectively on 20 consecutive DMD carriers. Results: The average time elapsed between cMRIs was 39 months. Overall, left ventricular ejection fraction (LVEF) increased in DMD carriers over time, though the improvement in LVEF did not reach significance (57% + 8 vs 59% + 6, p=0.2). However, subgroup analysis of 16 DMD carriers with reduced LVEF (defined as LVEF &lt;62%) demonstrated significant improvement in LVEF following RAAS inhibition (54% + 6 vs 58% + 7; p= 0.004). DMD carriers with reduced LVEF additionally demonstrated a significant decrease in left ventricular end systolic volume index (LVESVi) after RAAS inhibition (38 + 10 vs 32 + 10 ml/m2; p= 0.013). Conclusions: DMD carriers with reduced LVEF showed significant improvement in LVEF and LVESVi following RAAS inhibition. Collectively, the data suggest that RAAS inhibition significantly improves left ventricular systolic function and significantly reduces maladaptive left ventricular remodeling and dilation in this population.
Abstract 11153: Massively Parallel, High-Throughput Approach for Identifying Defective <i>KCNH2</i> (hERG) Variants
Authors: Rizwan Ullah, Chai Ng, Jessica Farr, Adam Hill, krystian kozek, Loren Vanags, Devyn Mitchell, Jamie Vandenberg, Brett Kroncke
Journal: Circulation (2021)

Introduction: Individuals with congenital long QT syndrome (LQTS) are at high risk for the life-threatening arrhythmia torsades de pointes . Loss-of-function KCNH2 (aka hERG ) variants that reduce repolarizing current, I Kr , are responsible for &gt;30% of LQTS cases with ~6% of sudden death in the young and ~1% in infants. Most KCNH2 variants are observed in some individual(s) making it difficult to obtain clinical evidence to assign pathogenicity; &gt;80% of KCNH2 missense variants in ClinVar are listed as variants of uncertain significance. To help adjudicate variants lacking in compelling clinical data, we demonstrate a method to characterize KCNH2 variant dysfunctions. Methods: We combined deep mutational scanning with a HA tagged KCNH2 construct to enable massively parallel characterization of channel trafficking of missense variants in KCNH2 . We have applied this method to the first 160 residues of KCNH2 ; 3,123 missense variants in total, a known hotspot for disease causing variants. For a subset of 458 non-redundant single nucleotide missense variants, we compared trafficking data, and in silico classifiers, with patch clamp data collected on the SyncroPatch platform. Results: Trafficking data is better than in silico features at predicting peak tail I Kr values, with an area under the receiver operating characteristic curve of &gt; 0.9 for trafficking data versus 0.8 for in silico feature. The Spearman correlation coefficients were 0.73 [0.67-0.78] compared to 0.51 [0.44-0.58] for trafficking and in silico predictions respectively. Our assay identified substitution sensitive regions, surrounded by more permissive residues. We also found substitution intolerant sites involved in networked hydrogen-bonding. Conclusion: A massively parallel trafficking assay can recapitulate most KCNH2 defects more effectively than in silico methods. Extended application of our method will enable the assessment of all missense variants in KCNH2 and other cardiac ion channels.
Covid-19: What next for the Valneva vaccine?
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Valneva's covid-19 vaccine looked set to be another effective tool in the fight to end the pandemic. But the UK's sudden decision to cancel the company's main order of 100 million doses threw a major spanner in the works. <b>Elisabeth Mahase</b> asks what this means for the company and the vaccine
Abstract 14214: Visualization and Quantification of Autogenic Cardiac Mechanical Waves
Authors: Cooper Moore, Andrew McCrary, Melissa LeFevre, Piers Barker, Olaf T Von Ramm
Journal: Circulation (2021)

Introduction: We have developed a visualization technique, High Speed Difference Imaging (HSDI) that has revealed many rapidly propagating phenomena throughout the cardiac cycle. We observed diastolic and systolic waves in adult volunteers and measured their velocities to determine the nature of the waves. We hypothesize from these early observations that these waves are autogenic shear waves that will propagate at higher velocities in systole. Methods: High frame rate ultrasound images were acquired using the T5 System with synchronous EKG. T5 is the Duke University Phased Array Research Ultrasound Scanner that can be configured to acquire real time, live images at rates up to 1000 B-Modes per second for adult cardiac applications. HSDI were generated in 10 volunteers in the AP4 view. A late diastolic shadow that propagated from apex to base in the lateral wall was characterized in all volunteers. A distinct early systolic shadow was able to be isolated in the lateral wall of five volunteers. The velocity of these shadows was calculated by measuring the length of the lateral wall along during its appearance and by counting calibrated timed frames while the shadow was visible. Results: The diastolic propagating shadow was observed in all ten volunteers in multiple cardiac cycles. The late diastolic shadow was measured propagating apex to base at an average velocity of 2.5 ± 0.5 m/sec. In the five volunteers with distinct systolic shadows, the propagating velocity was measured to be 4.8 ± 0.7 m/sec. The average ratio of systolic shadow propagation velocity to diastolic in the five patients was 1.95. These propagation velocities are comparable to published myocardial shear wave velocities in humans. Conclusions: The propagation velocity of these waves doubles in systole when the myocardial tissue is stiffened, and the velocities measured are within the range of reported shear wave velocities in myocardium. We conclude that high frame rate ultrasound imaging may allow for the visualization and quantification of autogenic cardiac shear waves.
Abstract 14292: Binge-on-Chronic Alcohol-Induced Gut Dysbiosis Results in Reduced Nitric Oxide Bioavailability and Endothelial Dysfunction
Authors: Zhen Li, Min Gu, David A Welsh, David J Lefer, Thomas E Sharp
Journal: Circulation (2021)

Introduction: Binge alcohol drinking adversely impacts cardiovascular (CV) homeostasis, leading to increased risk of CV diseases. It is also well-established that chronic alcohol consumption causes gut dysbiosis. However, the effects of alcohol-induced gut dysbiosis on vascular endothelial function remains unknown. Methods: We studied C57BL/6 mice at 10 weeks of age for these studies with n = 8-18 mice per group. Mice underwent a binge-on-chronic alcohol (BoCA) feeding protocol for 20-days and received either vehicle or probiotic treatment. Aortic vascular reactivity (acetylcholine and sodium nitroprusside), plasma nitrite (HPLC) and 8-isoprostane levels (ELISA) were measured. Another group of mice (n = 11-12 per group) received broad-spectrum antibiotic treatments followed by gut microbiotic transplants from either pair-fed or BoCA fed donor mice and plasma nitrite levels were measured to assess vascular function. Results: BoCA resulted in impaired endothelium-dependent vascular relaxation which was accompanied by reduced plasma nitrite levels. Probiotic treatment significantly attenuated vascular dysfunction, increased plasma nitrite and reduced 8-isoprostane levels. Further, mice receiving gut microbiotic transfer from alcohol-treated donor mice exhibited reduced circulating nitrite levels when compared to those who receiving the transfer from pair-fed donor mice. Conclusions: Our data demonstrate that BoCA consumption induced vascular injury resulting in reduced NO bioavailability, impaired vascular relaxation, and elevated oxidative stress which was attenuated by probiotic treatment. Mice receiving gut microbiotic contents from BoCA fed donor mice displayed reduced NO bioavailability, suggesting that gut dysbiosis is involved in the detrimental cardiovascular effects of BoCA. Further studies are underway to define the mechanisms by which alcohol-induced gut dysbiosis promotes cardiovascular disease.
Lesions at the appendiceal orifice – the Achillesʼ heel of endoscopic resection?
Authors: Arthur Schmidt
Journal: Endoscopy (2021)

Since the introduction of endoscopic full-thickness resection (EFTR) using the full-thickness resection device (FTRD), many studies have investigated the technique for its efficacy and safety in various indications. However, it is a matter of debate as to whether it should be used for endoscopic resection of lesions involving the appendiceal orifice.
Pomalidomide Promotes the Maturation of Healthy Donors and Multiple Myeloma Patients Derived-Dendritic Cells
Authors: Xi Wang, Feifei Che, Wanjun Cao, Zichen Ye, Hong Zheng, Xiaobing Huang, Rong Xiao, Wen Wang, Xuemei Ye, Lin He, Jingying Dai
Journal: Blood (2021)
Abstract P346: Ferroptosis Is Critical In Diabetic Atherosclerosis Through Heme Oxygenase 1 Regulated Lipid Peroxidation Pathway
Authors: Zhijun Meng, Zhen Zhang, Jumpei Tsukuda, Xin L Ma, Yajing Wang
Journal: Circulation Research (2021)

Introduction: The patients with diabetes dramatically accelerates atherosclerosis. Although improved diabetes treatment strategy has prevented the pathogenesis, diabetic atherosclerosis is still the main cause of morbidity and mortality. It is urgent to clarify its in-depth mechanism and identify new therapeutic targets for preventing diabetic atherosclerosis. Hypothesis: We assessed the hypothesis that ferroptosis and HMOX1 may be implicated in diabetes atherosclerosis through comprehensive in-depth bioinformatics analysis. Methods and Results: Analysis of Gene expression profiles (GSE30169 and GSE6584) provided a total of 91 differentially expressed genes (DEGs) including 68 up-regulated and 23 down-regulated genes (A). Ferroptosis, a type of programmed cell death dependent on iron, and HMOX1, a gene that encodes heme oxygenase, were identified as key factors in diabetes atherosclerosis (B). To explore the potential mechanism, we measured iron content and reactive oxygen species (ROS) generation and conducted a lipid peroxidation assay. Compared with animals on a normal diet (ND), ferroptosis and HMOX1 expression in ApoE -/- mice on high-fat diet (HFD) were significantly increased (C, n = 3). Ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated the diabetic atherosclerosis area in HFD animals (D, n = 5, P &lt; 0.01 vs HFD). In addition, Fer-1 restored the ferroptosis-related protein (GPX4 and SLC7A11) with high glucose high lipid (HGHL) treatment in Mouse arterial endothelial cells (MAECs) (E, n=6). More importantly, HMOX1 deficiency rebalanced Fe 2+ overload, decreased iron content, reduced ROS, and alleviated the lipid peroxidation, which led to the reduction of ferroptosis in diabetic endothelial cells (F). Conclusions: We demonstrate that ferroptosis is critical in diabetic AS progression and HMOX1 is an implicated factor responsible for ferroptosis in diabetic AS development, suggesting HMOX1 may serve as a potential therapeutic or drug development target.
Abstract 11136: Obstructive Sleep Apnea in Aortic Dissection
Authors: Evan Friend, Kinnari Murthy, Pavel Leinveber, Anna Svatikova, John Hochhold, Gregg S Pressman
Journal: Circulation (2021)

Background: Obstructive sleep apnea (OSA) imposes an afterload burden on the left ventricle and increases the pressure gradient across the intrathoracic aorta. This might increase the likelihood of aortic dissection (AD). We hypothesized that patients with acute AD would have a high prevalence of previously undiagnosed OSA and a largely nocturnal presentation. Methods: 40 consecutive, consenting subjects with acute AD who survived to hospital discharge were collected from 4 institutions. Mean age was 57 (range 28-75), 24 were male. 25 had type A dissection and 15 type B. 37 completed the modified Berlin Questionnaire and 30 had attended overnight polysomnography. Presenting CT scans had aortic diameter measured at a) the sinotubular junction b) ascending aorta c) origin of innominate d) mid-arch e) origin of left subclavian f) mid-descending aorta g) level of diaphragm; CT scans at 3 months were available in 24 subjects. Results: AHI ranged from 0 - 89; prevalence of OSA (defined by apnea-hypopnea index [AHI] &gt; 5) was 63%. There were no differences in aortic diameter at any level comparing OSA vs non-OSA, regardless of AHI cutoff (&gt;5, &gt;15, &gt;30; figure). Over time aortic diameter decreased at the level of the sinotubular junction and ascending aorta (expected - due to surgery). Whether dissection occurred during overnight hours (10 PM - 7 AM) did not differ by presence/absence of OSA (regardless of AHI cutoff). In those with high-risk Berlin questionnaires (&gt;=2 categories positive) 10/21 (48%) dissections occurred during sleeping hours vs 2/13 (15%) in low risk Berlin group (p = 0.08, Fisher’s exact test). Conclusions: Among patients with acute AD the prevalence of OSA was high. Aortic diameters, however, were not different according to level of AHI. Presence of OSA defined by polysomnography was not associated with a nocturnal presentation in this sample.