tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer
Authors: Emese Zsiros, Sarah Lynam, Kristopher M. Attwood, Chong Wang, Shanmuga Chilakapati, Eduardo Cortes Gomez, Song Liu, Stacey Akers, Shashikant Lele, Peter J. Frederick, Kunle Odunsi
Journal: JAMA Oncology (2020)

Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies.To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer.This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020.Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent.Primary outcomes were objective response rate (ORR) and progression-free survival (PFS).Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]).In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer.ClinicalTrials.gov Identifier: NCT02853318.
Abstract 13898: A Comparison of Rate Control Agents in Patients With Atrial Fibrillation: Follow-up Investigation of Affirm Study
Authors: Ninad Zaman, Gerald Naccarelli, Andrew Foy
Journal: Circulation (2020)

Introduction: There is limited data from randomized controlled trials comparing rate control agents in patients with atrial fibrillation (AF). We used patient-level data from the AFFIRM trial to compare outcomes in patients randomized to the rate control arm who were treated with a single rate control agent at baseline, including beta-blockers (BB), calcium channel blockers (CCB), or digoxin. Methods: Patient-level data from the AFFIRM trial was provided through the NHLBI BioLINCC biologic specimens and data repository information coordinating center. Different data sets were used to obtain the data for analysis. The independent variable for this analysis was the initial study drug used, which was classified as BB, CCB, or digoxin. The dependent variables were time to first hospitalization and time to death. Cox proportional hazards survival models were used to control for baseline differences between groups. Results: We analyzed 1144 out of 2027 participants assigned to the rate control group who were on a single rate control agent at the start of the trial. 485 (42.5%) participants were in the BB group, 344 (30%) in the CCB group, and 315 (27.5%) in the digoxin group. The mean age was 69.6 ± 8.0 and the majority of participants (62.9%) were male. Significant differences in baseline characteristics were present between groups, including sex, history of heart disease, left ventricular (LV) ejection fraction, LV diastolic dimension, and history of pulmonary disease. Hospitalization and death occurred in 55.9% and 12.5% of those in the BB group, 58.4% and 16.7% in the CCB group, and 55.2% and 21.1% in the digoxin group, respectively. After adjustment for differences in baseline characteristics, there were no significant differences in time to hospitalization or death for any group compared to another. Conclusions: In the AFFIRM trial, the initial rate control drug used was not associated with statistically significant differences in time to hospitalization or death after controlling for differences in baseline characteristics. There is limited data at present to guide the selection of rate control agents in patients with AF.
Abstract 17303: Longitudinal Cerebral Oxygen Metabolism in Congenital Heart Disease
Authors: Jessie Mei Lim, Davide Marini, Amandeep Saini, Stephanie Au-Young, Steven Fan, Vann Chau, Steven Miller, Mike Seed
Journal: Circulation (2020)

Background: Brain growth differences are apparent between different types of cyanotic congenital heart disease, but the underlying mechanism remains unclear. Here, we explored and characterized longitudinal cerebral hemodynamic and oxygen metabolism profiles and their relationships to brain growth patterns in infants with single ventricle physiologies (SV) and transposition of the great arteries (TGA). We hypothesized that there are marked differences in cerebral oxygen metabolism in those with SV compared with TGA. Methods: Cerebral blood flow (CBF), oxygen delivery (CDO2) and consumption (CVO2) and brain growth were measured in 103 term newborns with SV and TGA using MRI at pre- and post-surgery and at follow-up. We measured whole brain size by segmenting a 3D steady state free precession acquisition. Cerebral blood flow was measured using phase contrast imaging of the neck vessels and cerebral venous blood oxygen saturation was derived from T2 oximetry of the superior sagittal sinus. TGAs were divided into those with and without ventricular septums. Results: CBF profiles were similar between the 3 lesion groups. Cerebral oxygen delivery trends increased but were not significantly different between cardiac groups. We observed that this may be mediated by different mechanisms: an increase in arterial saturation in TGAs, and an increase in hemoglobin concentration in SVs. Cerebral oxygen consumption in SV infants remained low (p = 0.54) while that of TGA increased over time (TGA IVS p &lt; 0.001; TGA VSD p &lt;0.001) (Fig. 1), mediated by an unchanging oxygen extraction fraction in SVs (p = 0.59). The SV cerebral oxygen consumption profile aligned with their declining brain weight z-score trajectory. Conclusions: In conclusion, there are characteristic differences in hemodynamic adaptations between SVs and TGAs. Changes in oxygen metabolism may be facilitating brain growth trajectories. This informs us of possible mechanisms involved during a time of critical brain development.
Abstract 13215: Gender-affirming Hormones Are Associated With Increased Risk of QT Prolongation in Transgender Females
Authors: Daniel Antwi Amoabeng, Ahmed Hanfy, Munadel Awad, Bryce D Beutler, Amneet Rai, David T Gbadebo, Michael Keogh
Journal: Circulation (2020)

Introduction: Women have a longer QT interval than men. This sex-specific difference is attributed to hormones associated with the biological female sex. Male-to-female transgender individuals often take antiandrogens such as spironolactone or goserelin in addition to estrogens to suppress testosterone effects while increasing feminine features. Effects of gender-affirming hormone therapy (GHT) on the QT interval in these individuals remains to be elucidated. Hypothesis: We assessed the hypothesis that the use of GHT is associated with an increased risk for QT interval prolongation in transgender females. Methods: We identified 46 transgender females through a search of the electronic medical records of a Veterans Administration hospital in Northern Nevada. Patients with a diagnosis of congenital long QT syndrome were excluded. Of these, 13 patients had ECGs before and after initiation of GHT and were included. We adapted the Tisdale score using the auto-calculated corrected QT interval (QTc) to estimate the risk of QT prolongation. Age, QTc, and Tisdale scores before and after GHT initiation were compared using the Wilcoxon signed-rank test. All tests were performed as two-tailed at a 5% level of significance. Results: All 13 study patients were taking estrogens. Of these, 3 (23.1%) were taking goserelin and 9 (69.2%) were taking spironolactone. Mean ± SEM age at ECG acquisition was 45.0 ± 4.4 and 47.7 ± 4.7 years before and after the initiation of GHT respectively. Mean ± SEM QTc after initiation of GHT was significantly higher compared to the baseline (467.5 ± 12.8 ms vs. 428.2 ± 7.1 ms) (Figure 1A). The average baseline Tisdale score was significantly smaller on follow-up (1-point vs. 3 points) (Figure 1B). Conclusions: GHT appears to be associated with increased QTc in transgender women. This needs to be interpreted with caution owing to the very small sample size in this study. Further studies to investigate the strength of this association, if it exists, are warranted.
Abstract 15843: A Novel Role for Telomerase in Calcific Aortic Valve Disease
Authors: Rolando A Cuevas, Luis HORTELLS, Camille Boufford, Cailyn Regan, Claire Chu, William Moorhead, mauricio rojas, Dennis Bruemmer, Thomas G Gleason, Cynthia St. Hilaire
Journal: Circulation (2020)

Introduction: Calcific aortic valve disease (CAVD) is a disorder characterized by the slow, but a progressive thickening of the aortic valve leaflet that develops into severe calcification. The only current therapy is aortic valve replacement. Telomerase is an enzymatic complex best known for its telomere-extending activities on the ends of chromosomes yet, the catalytic subunit (TERT) has been implicated in multiple non-canonical transcriptional and epigenetic activities, including priming of mesenchymal stem cells (MSCs) to differentiate into osteoblasts, and transcriptional regulation of inflammatory genes. Hypothesis: We hypothesize that non-canonical TERT activity contributes to the progression of CAVD. Methods: We performed biochemical assays to study the role of TERT in the calcification process using primary tissues and valve interstitial cells (VICs) from control and CAVD patients, smooth muscle cells (SMCs) from WT and Tert knockout mice, and mesenchymal stem cells (MSCs). Results: We found that TERT protein is highly expressed in calcified aortic valves and VICs isolated from patients with calcified valves, compared to healthy valves. VICs can be induced to calcify under osteogenic differentiation conditions, and we found that TERT accumulated after fourteen days in this culture, with no effect on either telomere length, proliferation, or senescence. We expanded the scope of our approach by evaluating TERT's influence on calcification of mice aortic smooth muscle cells (mSMCs). We found WT mSMCs readily calcified in vitro, but mSMCs from Tert knockout mice did not, and Tert deletion also reduced valve calcification in a Ldlr / Tert double knockout mice model compared to Ldlr knockout alone. In VICs, shRNA mediated TERT downregulation reduced expression of RUNX2 . Finally, we found that inflammatory signals intensify in vitro calcification, induce TERT expression, and we show evidence that TERT interacts with STAT5. Conclusion: Our data suggest that TERT is required for valve calcification by stimulating transcriptional pathways promoting the osteogenic transition of quiescent VICs into calcifying VICs in the aortic valve. These results indicate that TERT is an active contributor to the calcification process of valve tissues.
Abstract 237: Curriculum Development of Pitt Bystander Response Education: Developing "Caring Leaders" Through Early Exposure to Cpr Fundamentals
Authors: Emily Hacker, Gillian Ahrendt, Jackson Mitzner, Clifton W Callaway, Ankur A Doshi
Journal: Circulation (2020)

Introduction: Fewer than 25% of US adults feel trained in bystander CPR (bCPR). Barriers include the lack of social acceptance of bCPR, poor understanding of Good Samaritan laws, and inadequate knowledge of the steps needed to help a patient suffering out-of-hospital cardiac arrest. Hypothesis: We developed a novel, streamlined curriculum for children ages 11-13 to introduce the principles of bCPR and frame it as a shared social responsibility, hoping to increase bystander response and motivate young citizens to seek future CPR certification. Methods: The curriculum development process employed the Assess Design Develop Implement Evaluate (ADDIE) method of the Instructional System Design (ISD) model. We used an iterative approach where the novel curriculum was developed and then presented to stakeholders for review, editing and revision. Stakeholders included experts in CPR training, educational theory and elementary/middle school education. Pre- and post- survey tools were designed to evaluate curriculum outcomes, using the same process. Upon completing the iterative review, the curriculum and surveys were prepared for a pilot implementation in a middle school setting. Results: Using the ISD approach, we consulted with 9 experts to design the CPR curriculum. Three curriculum goals were identified: awareness, social responsibility and training. The novel curriculum will meet these goals through a single 50 minute in-class session of didactic, technique demonstration of compression-only CPR, and hands-on practice with manikins. Due to the present global pandemic, the curriculum has not yet been implemented as planned. Current efforts are being made to determine the feasibility of potential future implementation of the program and/or virtual options due to need for social distancing. Conclusions: An iterative process can be used to bring together multiple stakeholders to design a novel, age appropriate CPR training curriculum. Another round of stakeholder review of the curriculum is planned post piloting prior to wider dissemination.
Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting
Authors: Maria L. Jaramillo, Zully Leon, Suzanne Grothe, Beatrice Paul-Roc, Abedelnasser Abulrob, Maureen O’connor Mccourt
Journal: Cancer Research (2006)

1243  mAbs directed to the epidermal growth factor receptor (EGFR) have been shown to have tumor-inhibitory potential. The mechanisms underlying this effect are not well understood. The anti-receptor antibody, 225 mAb, is known to block binding of ligand to the EGFR, thus preventing ligand-induced receptor tyrosine kinase activation. However, the effect of this neutralizing antibody on EGFR endocytosis, trafficking and degradation remains unclear. Here, we demonstrate that endocytosis of 125I-225 mAb occurs, with the ratio of internalized-to-cell surface 125I-225 mAb reaching approximately 0.4 at steady state. Using recycling assays, we show that internalized 125I-225 mAb is recycled to the surface much more efficiently than internalized 125I-EGF. Also, in contrast to EGF, internalization of 125I-225 mAb is independent of receptor tyrosine-kinase activity, as evidenced by its insensitivity to AG1478, a specific tyrosine kinase inhibitor for EGFR. Analysis of EGF receptor cell surface levels showed that treatment with 225 mAb results in a 30-40% decrease in surface EGFR and a concomitant increase in surface erbB2. Taken together, these data indicate that 225 mAb induces internalization and down-regulation of EGFR via a mechanism distinct from that underlying EGF-induced EGFR internalization and down-regulation.
Abstract 310: Validation of the Cardiac Arrest Hospital Prognosis (CAHP) Score in an American Out-of-hospital Cardiac Arrest Cohort: Results From a Large Single Center Cardiac Arrest Registry
Authors: Jason J Grady, Katie A Atwell, Tomo Oshimura, Nima Ghasemzadeh
Journal: Circulation (2020)

Background: The cardiac arrest hospital prognosis (CAHP) score has been shown in French studies to predict neurologic outcomes in patients who suffer an out-of-hospital cardiac arrest (OHCA), but this score has not been studied in an American cohort. We aimed to validate the CAHP score in an independent, single center, large cardiac arrest registry. Methods: Between January 2015 to June 2020 there were 925 patients who suffered OHCA and were transferred to Northeast Georgia Medical Center out of whom 450 patients survived to hospital admission. Cerebral Performance Category (CPC) score was used for assessment of neurologic outcome at discharge ranging from 1-5. The primary endpoint was poor neurologic outcome defined as CPC 3-5. Logistic regression was performed to identify independent predictors of poor neurologic outcome. Results: Included patients were mostly male 57% (256 of 450) with a mean age of 52±15. STEMI was present on 11% (51 of 450) and a shockable rhythm on 35% (150 of 450) of patients. Targeted temperature management (TTM) and a mechanical compression device (MCD) were used in 72% (327 of 450) and 74% (336 of 450) respectively. 76% (344 of 450) had a CPC of 3-5 at discharge. After adjusting for covariates, including gender, BMI, serum lactate level, witnessed arrest status, STEMI on ECG, and use of MCD and TTM, the only independent predictors of a CPC of 3-5 were CAHP score (p&lt;0.001), witnessed cardiac arrest, (p=0.039, OR: 0.45) and STEMI on admission ECG (P=0.001, OR: 0.22). Compared with CAHP&lt; 150, CAHP 150-200 and CAHP&gt;200 were associated with a 12-fold (p&lt;0.00001) and 79-fold (p&lt;0.00001) increased risk of poor neurologic outcome. Area under ROC curve for CAHP score predicting neurologic outcome was 0.92 (95% CI: 0.89-0.94). Conclusion: Here we show, for the first time, in an independent, large American cardiac arrest registry that CAHP score predicts neurologic outcomes in patients with OHCA. Further research is needed to assess how this prognostication tool would help clinicians decide on early vs. delayed invasive strategy in patients with OHCA admitted to hospitals across the U.S.
SIRT1 deacetylates RORγt and enhances Th17 cell generation
Authors: Hyung W. Lim, Seung Goo Kang, Jae Kyu Ryu, Birgit Schilling, Mingjian Fei, Intelly S. Lee, Amanuel Kehasse, Kotaro Shirakawa, Masaru Yokoyama, Martina Schnölzer, Herbert G. Kasler, Hye-Sook Kwon, Bradford W. Gibson, Hironori Sato, Katerina Akassoglou, Changchun Xiao, Dan R. Littman, Melanie Ott, Eric Verdin
Journal: The Journal of Experimental Medicine (2015)

The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance. Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis. Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORγt, the signature transcription factor of Th17 cells. SIRT1 increases RORγt transcriptional activity, enhancing Th17 cell generation and function. Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis. Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells. These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity.
Abstract 13482: The Size of Circulating Microparticles and Cardiac Function in Patients With Cardiac Surgery
Authors: Jingsong Ou, Jian Ma, Ya-Ting Chen, Chao Chen, Yu-Quan Li, Hao-Xiang Yuan, Zhijun OU
Journal: Circulation (2020)

Introduction: We previously demonstrated that circulating microparticles (MPs) from cardiac surgery impaired vasodilation. The usages of positive inotropic drugs and the NT-proBNP levels are the important parameters representing cardiac function after cardiac surgery. However, the relationship between the size of MPs and the usages of positive inotropic drugs and the NT-proBNP levels in patients with cardiac surgery remains unknown. Hypothesize: The size of circulating MPs may correct with the usages of positive inotropic drugs and the NT-proBNP levels in patients with cardiac surgery. Methods: 103 patients undergone cardiac surgery and 56 healthy subjects were enrolled. The blood was collected from healthy subjects and patients before (pre-op) and after operation 12h (post-op 12h) and 72 h (post-op 72h). The MPs were isolated by differential centrifugation. The concentration and size distribution of MPs were detected by nanoparticle tracking analysis system. The clinical data were collected and the correlation was performed between the MPs and the clinical data. Results: The level of MPs was increased in patients compared with healthy subjects. There was no significant difference of MPs concentration among the different time points (per-op, post-op 12h and post-op 72h) in patients. The MPs were divided into four groups according to the size (0-100nm, 100-200nm, 200-300nm and 300-400nm). The levels of “100-200nm” MPs were decreased in post-op 12h and post-op 72h groups compared with per-op group, but the levels of “200-300nm” MPs were increased after operation. In post-op12h group, the concentration of “0-100nm” MPs was negatively correlated with the NT-proBNP levels, the dose of dopamine, norepinephrine and milrinone, and the level of “200-300nm” MPs were positively correlated with NT-proBNP levels. In post-op72h group, the level of “0-100nm” MPs was negatively correlated with NT-proBNP levels, and the concentration of “200-300nm” MPs was negatively correlated with the dose of dobutamine. Conclusion: Our data demonstrated that the size of circulating MPs is corrected with the usages of positive inotropic drugs and the NT-proBNP levels in patients with cardiac surgery, and may predict the cardiac function after cardiac surgery.