tbuckley/cabot-search huggingface dataset:
SURG-09. SUCCESSFUL SAFETY AND EFFICACY OF GAMMATILE INTRACRANIAL BRACHYTHERAPY IMPLANTED DURING AWAKE CRANIOTOMY
Authors: Shearwood McClelland III, Ulysses Gardner, Yi Le, Sook Kien Ng, Mitesh Shah, Gordon Watson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION GammaTile intracranial brachytherapy utilizing cesium-131 seeds has demonstrated encouraging safety and local control results in a single-arm precommercial study, and recently received Food and Drug Administration clearance. The authors report the first case of GammaTile intraoperative brachytherapy performed during an awake craniotomy. METHODS A 50-year-old man suffered a generalized tonic-clonic seizure while a vehicle passenger. MRI revealed a 2.8 cm left lateral frontal lesion nearing his Broca’s area. Open brain biopsy revealed IDH-wildtype MGMT unmethylated GBM. Unfortunately, despite several interventions (awake craniotomy, adjuvant chemoradiation with temozolomide, Avastin, tumor treating fields) he suffered tumor progression near the left parietal resection cavity. Due to the location of this tumor, re-resection was planned with awake craniotomy and language mapping. A preoperative planning session involving Radiation Oncology and Neurosurgery identified the area of the expected postoperative bed, and consequently five GammaTiles were ordered, each containing 4 cesium-131 3.5 U seeds. RESULTS During surgery, once the tumor was mapped, bipolar stimulation was performed while the patient spoke in complete sentences until going into speech arrest on the posterior edge of the gyrus, indicative of language cortex. Following this mapping, microsurgical maximal safe resection occurred, after which areas at risk for tumor residual/recurrence were determined in consultation with Radiation Oncology. Subsequently, Neurosurgery placed all five GammaTiles (20 cesium-131 seeds total) in customized forward fashion to optimally cover the dosimetric needs of these areas. Following GammaTile placement, closure was completed and radioactive surveys of the room remained within state statue. Postoperative dosimetry yielded excellent coverage, and speech function was maintained. CONCLUSIONS The first reported case of GammaTile intraoperative brachytherapy during awake craniotomy supports the safety and feasibility of this treatment strategy. This case indicates that for patients with tumors adjacent to eloquent cortex, awake craniotomy can allow for maximum safe resection and implantation of intraoperative brachytherapy.
Abstract 13431: Gain-of-Function Mutations in RNA Binding Motif 20 Result in Cardiac Remodelling and Pathogenesis in Mice
Authors: Yanghai Zhang, Chunyan Wang, Mei Methawasin, Camila U Braz, Jeffrey Gao-Hu, Betty Yang, Joshua Strom, Timothy A Hacker, Hasan Khatib, Henk L Granzier, Wei Guo
Journal: Circulation (2021)

Gain-of-function mutations of a gene result in new molecular function. Genetic studies show that mutations in a gene named as RNA binding motif 20 (RBM20) are associated with dilated cardiomyopathy (DCM). To test whether Rbm20 mutations are responsible for cardiac remodelling and potential underlying mechanisms, we selected two mutations (S637A and S639G) located in arginine/serine-rich domain of RBM20 and generated two knock-in mouse models ( Rbm20 S637A and Rbm20 S639G ) respectively. Both mouse lines were subjected to histological and anatomical analysis as well as cardiac function assessment with echocardiography. The results revealed that heterozygous (HT) and homozygous (HM) male and female mice from both lines displayed DCM phenotype with enlarged left ventricular (LV) chamber, thinner LV walls and reduced ejection fraction. Interestingly, we observed that Rbm20 S639G mice manifested more severe phenotype than that in Rbm20 S637A mice. Rbm20 S639G HM mice exhibited higher mortality rate (~50%) than that (~34%) in Rbm20 S637A HM mice at an early age (&lt;100 days). Differentially expressed and spliced genes from RNA-seq data are involved in arrhythmia, cardiomyopathy, and sudden death based on Human Phenotype Ontology enrichment analysis (FDR≤0.05) in both lines. Immunofluorescent analysis in tissues and single cardiomyocytes respectively showed both mutations promote RBM20 nucleocytoplasmic trafficking and protein condensates, suggesting they are gain-of-function mutations, leading to high mortality rate at younger age. Both mutations also interrupted the alternative splicing of TTN and calcium handling genes. Force measurements and Ca 2+ transient evaluation of intact myocytes showed that the reduced cellular diastolic stiffness and impaired contractility in HT and HM mice. Studies suggested that phosphorylation of RS domain is critical for protein trafficking. We then performed mass spectrometry on the in vitro expressed RBM20 and identified phosphorylation on S637 and S639. Phosphomimetic assay showed that phosphorylation was not responsible for RBM20 trafficking and condensates. Together, we reported a new mechanism by which cardiac genetic mutations causes protein trafficking and aggregation in cardiac remodelling.
Abstract 14409: Elucidating Clinical Phenotypes of Patients With Mixed Shock Admitted to Cardiac Intensive Care Units: Insights From the Critical Care Cardiology Trials Network
Authors: Aditya Dewanjee, Ajar Kochar, David D Berg, Erin A Bohula, Jeong-Gun Park, Sean Van Diepen, Jason N Katz, David A Morrow, Shashank S Sinha
Journal: Circulation (2021)

Background: Emerging data suggests that patient with mixed cardiogenic and vasodilatory shock have high morbidity and mortality; however, this population is still poorly understood and is not well-characterized. Methods: The Critical Care Cardiology Trials Network is a multicenter network of advanced cardiac intensive care units (CICUs) in North America coordinated by the TIMI Study Group. Each CICU contributed an annual 2-month period of all consecutive medical CICU admissions from 2017-2020 (n=13,300). Mixed shock (MS) subjects were stratified into those with acute MI (AMI-MS) and those without (non-AMI-MS). Results: Among 3884 CICU admissions with shock, 840 (22%) presented with MS; 169 AMI-MS and 671 non-AMI-MS. Mean age was 66y, 37.1% were female, and 69.5% were white. Median Sequential Organ Failure Assessment was 10.0 (25 th -75 th %ile, 7.0-12.5). On presentation, AMI-MS had more end-organ injury: lactate (3.5 vs. 2.7, p &lt; 0.01) &amp; AST (126 vs. 54, p &lt; 0.01). AMI-MS had fewer CV &amp; non-CV comorbidities ( p &lt; 0.01 for all). Sepsis was less common in AMI-MS (47.8% vs. 67.6%, p &lt; 0.0001). Use of advanced ICU therapies was high, as 25.4% overall cohort required renal replacement therapy (RRT). AMI-MS required more mechanical ventilation (81.1% vs. 67.5%, p &lt; 0.001), invasive cardiac procedures (76.3% vs. 16.2%, p &lt; 0.0001), and temporary mechanical support (tMCS) (56.8% vs. 16.7%, p &lt; 0.0001). Both AMI-MS and non-AMI-MS patients had high in-hospital mortality (50.3% [95% CI 42.5% - 58.1%] &amp; 43.5% [95% CI 39.7% - 47.4%], respectively). AMI-MS patients with a worst pH &lt; 7.25, ≥ 3 pressors, and RRT use have a 4.9-fold, 3.9-fold, and 2.9-fold risk of in-hospital mortality, respectively (Figure). Conclusion: In a contemporary multicenter analysis of advanced CICUs, patients with mixed shock have high in-hospital mortality and frequent need for advanced ICU therapies. Patients with AMI-MS present with particularly high shock severity and subsequent resource utilization.
Abstract 13526: Left Atrial Appendage Emptying Velocity is a Predictor of Atrial Fibrillation Recurrence in Patients Undergoing Catheter Ablation
Authors: Sahith Reddy Thotamgari, Javaria Ahmad, Aakash Sheth, Danish Bawa, Sindhu Thevuthasan, Paari Dominic
Journal: Circulation (2021)

Introduction: Low left atrial (LA) voltage is known to predict Atrial Fibrillation (AF) recurrence after catheter ablation (CA); however, its measurement involves invasive electrophysiology study (EPS). Left Atrial Appendage (LAA) emptying velocities are routinely measured during pre-procedural Transesophageal Echocardiography (TEE). We sought to assess the association between LAA velocities and AF recurrence after CA. Hypothesis: Pre-procedural LAA emptying velocity is a predictor of AF recurrence in patients undergoing CA. Methods: A total of 263 consecutive patients who underwent CA for AF between 2014 and 2020 were included. Baseline clinical characteristics and echocardiographic data of the patients were obtained by chart review. LAA emptying velocities were obtained from TEE. LA voltage was obtained during the EPS. Chi-square test and nominal logistic regression were used for statistical analysis. A sensitivity of 80% on the ROC curve was used for determining LAA velocity cut-off. Results: Mean patient age was 60.8±10.9; 34% were female. Mean LAA emptying velocity was 48.0±20.4. Mean average total voltage (Vavg) of LA was 1.58±1.05. There was a significant positive linear correlation between LAA velocity and LA Vavg (p=0.004*). A total of 68 (26%) patients had recurrence after CA. Patients with lower LA Vavg had increased AF recurrence compared to patients with higher LA Vavg (p=0.004*). In the multivariable model, after adjusting for HTN, CAD, HFrEF, and DM, LAA emptying velocity of ≥52.3 was associated with decreased AF recurrence post-ablation (OR 0.31; 95% CI 0.15-0.66; p = 0.002*). There were 190 (73%) patients in normal sinus rhythm during EPS mapping, and sensitivity analysis of these patients showed that LAA velocity ≥52.3 remained associated with decreased AF recurrence (OR 0.35; 95% CI 0.15-0.82; p = 0.01*). Conclusions: LAA emptying velocity measured during pre-procedural TEE can serve as a predictor of AF recurrence in patients undergoing CA.
Dnmt3a Mutations in the Hematopoietic System Promote Colitis-Associated Colon Cancer: A Model of Clonal Hematopoiesis in Solid Tumors
Authors: Yang Feng, Rachel Newsome, Troy Robinson, Robert L. Bowman, Ashley Zuniga, Kendra Hall, Cassandra Bernsten, Daniil Shabashvili, Kathryn Krajcik, Chamara Gunaratne, Zachary Zaroogian, Kartika Venugopal, Heidi Casellas Roman, Ross L. Levine, Alberto Riva, Daniel Kopinke, Christian Jobin, Dorina Avram, Olga A Guryanova
Journal: Blood (2021)
Abstract 12881: Abnormal Retinal Perfusion Indices by Optical Coherence Tomography Angiography (OCTA) Associate With Abnormal Coronary Flow Reserve
Authors: Brittany N Weber, Omar AbuQamar, Luísa S Mendonça, Leanne Barrett, Laurel Martell, Jenifer M Brown, Sanjay Divakaran, Courtney Bibbo, Evan Wilson, Astrid Werner, Alexander Huther, Katherine P Liao, Jay Duker, Rahul C Deo, Nadia Waheed, MARCELO DI CARLI
Journal: Circulation (2021)

Background: Retinal microvascular evaluation could serve as a marker for cardiovascular disease risk. OCTA is a noninvasive method to quantitatively assess the retinal microvasculature. Coronary flow reserve (CFR), an integrated measure of focal, diffuse, and small-vessel coronary artery disease, identifies patients at risk for cardiac death. We aimed to identify associations between OCTA findings and CFR in patients undergoing cardiac positron emission tomography (PET) testing. Methods: Subjects (n=60) underwent a stress myocardial perfusion PET scan to quantify CFR and OCTA of both eyes on same day. CFR is the ratio of myocardial blood flow at peak stress compared to rest and adjusted for baseline cardiac work. OCTA scans were analyzed using a custom-built software to quantify foveal avascular zone (FAZ) geometry and vessel density metrics in the retina, reflecting retinal microvasculature. We used Spearman to correlate markers of retinal microvasculature with CFR. Results: Demographics of enrolled subjects are shown in Table I. Baseline cardiac risk factors were common and 22 (37%) subjects had an abnormal stress test. Retinal perfusion as indicated by the vessel index (ρ=0.35, p=0.006) and vessel diameter index (ρ=0.27, p=0.039) in the superficial 6x6 mm slabs were positively correlated with CFR. There was a trend towards negative association between FAZ area in the retina slab and CFR (ρ= -0.17, p=0.1). Conclusions: CFR was correlated with retinal perfusion indices based on OCTA, suggesting a relationship between coronary and retinal vascular health. These data provide potential insight into systemic vascular health and could provide an additional tool to assess cardiac risk.
Abstract 9738: Impact of Bleeding Event for New Cancer Diagnosis in Patients with Coronary Artery Disease Who Underwent Percutaneous Coronary Intervention
Authors: Yuya Sakuma, Takeshi Shimizu, Yuta Kurosawa, Himika Ohara, Yukiko Sugawara, Koichiro Watanabe, Yuki Muto, Yusuke Kimishima, Tomofumi Misaka, Akiomi Yoshihisa, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2021)

Background: Patients with coronary artery disease who underwent percutaneous coronary intervention (PCI) are at high risk of bleeding due to antithrombotic therapy. However, the impact of bleeding event for new cancer diagnosis in patients after PCI remains unclear. Methods and Results: Consecutive 1623 patients with coronary artery disease who underwent PCI (mean age, 69.3 years; male gender, 78.5%) were enrolled. We examined a relationship between bleeding events and new cancer diagnosis. During a mean follow-up period of 48 months, 139 (8.6%) experienced bleeding events of Bleeding Academic Research Consortium (BARC) type-2/3/5, including 48 (3.0%) with BARC type-2 bleeding. Patients with bleeding event of BARC type-2/3/5 were older (72.4 vs. 68.9 years, P = 0.001), and higher prevalence of being at Academic Research Consortium criteria for high bleeding risk (72.3% vs. 46.4%, P &lt; 0.001) than those without bleeding event. Among 1623 patients, 133 (8.2%) were diagnosed as having new cancer. The cumulative incidence of new cancer diagnosis was higher in patients with bleeding event of BARC type-2/3/5 than in those without bleeding event (P = 0.002, left figure). In addition, the cumulative incidence of new cancer diagnosis was higher in patients with bleeding event of BARC type-2 than in those without bleeding (P = 0.016, right figure). In the multivariate Cox proportional hazard analysis after adjusting for confounding factors, bleeding events of BARC type-2/3/5 and type-2 were independent predictors of new cancer diagnosis (hazard ratio 2.00, P = 0.007 and hazard ratio 2.25, P = 0.039, respectively). Conclusion: In patients with coronary artery disease after PCI, both major and minor bleeding events were associated with new cancer diagnosis. Even a minor bleeding event should be taken care as the first manifestation of underlying cancer after PCI.
Abstract 10621: Prediction of Incident Atherosclerotic Cardiovascular Disease Using Traditional and Polygenic Risk Score Modeling: The Million Veteran Program Experience
Authors: Daniel C Posner, Jason L Vassy, Michael J Pencina, Themistocles L Assimes, Ashley Galloway, Yuk-lam Ho, David R Gagnon, Juan P Casas, Scott M Damrauer, Michael Gaziano, Kelly Cho, Peter W Wilson, Yan V Sun
Journal: Circulation (2021)

The prediction of myocardial infarction (MI), acute ischemic stroke (AIS), cardiovascular (CVD) death, and 3-point MACE (MI, AIS, or CVD death) in Million Veteran Program (MVP) participants over 8 years of follow up was evaluated using environmental/traditional risk factors (“E”), polygenic risk scores (“G”), and a combination of both approaches (“GxE”). Individuals free of atherosclerotic cardiovascular disease (ASCVD) at baseline were included. Risk factor levels for the participants close to the time of MVP enrollment for age, sex, systolic blood pressure, cholesterol, HDL cholesterol, smoking status, and diabetes status were analyzed. Outcomes were determined from VA electronic record data, Medicare/Medicaid data, and the National Death Index. Analyses were undertaken separately for non-Hispanic European (EUR), African American (AFR), and Hispanic (HIS) participants. There were 157,941 veterans at risk with 8,157 MI events, 2,024 AIS events, 1,778 CVD deaths, and 9,350 3-pt MACE events over 8 years of follow-up. The overall results showed good performance with the environmental model for all three racial-ethnic groups, with C-statistics ranging from 0.69 to 0.77. The G models showed very modest prediction capabilities and similarly modest improvement in the combined GxE models. In conclusion, traditional risk factor modeling has been shown to be highly effective and, in the MVP experience, the additional impact of genetic or genetic interaction information was small.
The Design of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Chinese Patients with Polycythemia Vera Resistant or Intolerant to Hydroxyurea (HU)
Authors: Jie Jin, Lei Zhang, Su-Jiang Zhang, Suning Chen, Ming-hui Duan, Jingjing Zhang, Wei Wang, Warren Shen, Oleh Zagrijtschuk, Raymond Urbanski, Albert Qin, Zhijian Xiao
Journal: Blood (2021)
Abstract 10573: Dietary 7-Ketocholesterol Exacerbates Myocardial Ischemia-Reperfusion Injury Through Macrophage-Mediated Inflammation in Mice
Authors: Tomoki Uchikawa, Tetsuya Matoba, Shunsuke Katsuki, Jun-ichiro Koga, Hiroyuki Tsutsui
Journal: Circulation (2021)

Background: Myocardial ischemia-reperfusion (IR) injury limits the beneficial effects of early reperfusion therapy for acute myocardial infarction. Emerging evidence suggests that 7-ketocholesterol (7-KC), one of the most common dietary oxysterols, has pro-inflammatory properties and correlates with cardiovascular diseases. However, the underlying mechanisms remain scant. Here we investigated the effects of 7-KC on myocardial IR injury in mice. Methods and Results: Wild type mice were fed either a control high-fat high-cholesterol diet (HFHCD) or HFHCD containing 7-KC (7KC-HFHCD) for three weeks. In a murine model of 30-min myocardial ischemia and subsequent reperfusion, dietary 7KC-HFHCD increased plasma 7-KC level (145 ± 89.7 ng/mL vs 399 ± 175 ng/mL, P&lt;0.0005, N=8) and infarct size after myocardial IR (52 ± 7.3% vs 64 ± 6.9%, P&lt;0.05, N=8-10) without affecting blood pressure and heart rate. The ratio of Ly-6C high inflammatory monocytes to total monocytes increased in 7KC-HFHCD group as assessed by flow cytometric analysis (49 ± 15% vs 61 ± 9.3%, P&lt;0.05, N=6). We then took a systems approach to explore the pro-inflammatory effects of 7-KC on macrophages and performed unbiased RNA-sequencing using murine peritoneal macrophages stimulated with 7-KC. Pathway analysis of differentially expressed transcripts revealed that 7-KC regulated the expression of transcripts related to inflammation, cholesterol biosynthesis and endoplasmic reticulum (ER) stress. We further validated in vitro that 7-KC induced ER stress, mitochondrial reactive oxygen species, and nuclear factor-kappa B activation associated with increased mRNA levels of pro-inflammatory cytokines such as MCP-1 and TNF-α in murine peritoneal macrophages. Administration of N-acetyl-L-cysteine (5mM), an antioxidant, decreased 7-KC-induced pro-inflammatory cytokines, and this decrease was not observed in Tlr4 -/- murine macrophages, or in macrophages transfected with liver X receptor siRNA. Conclusions: Dietary 7-KC exacerbated myocardial IR injury through macrophage-mediated inflammation in mice. Oxidative stress is involved in the 7-KC-induced pro-inflammatory response in macrophages. Dietary oxysterols are a promising therapeutic target for IR injury.
Abstract 9771: Novel Contribution of an Epigenetic Factor "g9a" in Pulmonary Arterial Hypertension
Authors: Charifa Awada, Yann Grobs, Sandra Breuils-bonnet, Vinod Krishna, Jey R JEYASEELAN, Francois Potus, Roxane Paulin, Steeve Provencher, Sebastien Bonnet, Olivier BOUCHERAT
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by an increased mean pulmonary artery (PA) pressure. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients exhibit a “cancer-like” hyperproliferative and apoptosis-resistant phenotype leading to pulmonary vascular remodeling. It is believed that these alterations are influenced by epigenetic processes. However, it is still not clear which gene are the drivers. “G9a”, a histone methyltransferase, is known to be overexpressed in different types of cancer, promoting cell survival and proliferation. Given the similarities between PAH and cancer, we hypothesized that G9a could be implicated in PAH progression and pathogenesis. Methods and Results: Using Western blot (WB) and immunofluorescence (IF), we showed that G9a is significantly upregulated in distal PAs and isolated PASMCs from PAH patients (n= 6-14, p&lt;0.01). Similarly, G9a was increased (p&lt;0.05) in three PAH animal models: monocrotaline (MCT), fawn-hooded rat (FHR) and mice exposed to chronic hypoxia. In vitro, pharmacological G9A inhibition using BIX01294 reduces PAH-PASMC proliferation (Ki67/ EdU assays, p&lt;0.001) and survival (Annexin V assay, p&lt;0.001). Through RNA sequencing analysis conducted in PAH-PASMCs treated or not with BIX01294, we found that upregulated genes were significantly enriched in “cholesterol biosynthesis” and “autophagy”. Consistently, G9a inhibition was accompanied by an increased lipid accumulation and an impaired autophagy flux as evidenced by the appearance of numerous cytoplasmic vacuoles positive for LC3-II (IF, WB), the accumulation of yellow puncta in PAH-PASMCs expressing the RFP-GFP-LC3 fusion protein, the unaffected LC3-II expression after adding chloroquine and the defect in cathepsin B and D maturation (WB). Same results were seen with UNC0642, another G9A inhibitor. In vivo , we showed that BIX01294 significantly improved established PAH in FHR (reduced RVSP and mPAP, increased SV and CO, by right heart catheterization, and attenuated pulmonary vascular remodeling, p&lt;0,001). Conclusion: We showed that G9a upregulation contributes to the pro-proliferative phenotype of PAH-PASMCs; and its inhibition represents a novel avenue to improve PAH.