tbuckley/cabot-search huggingface dataset:
Abstract 10942: Comparison of Long-Term Prognostic Impact of 6 Major Cardiovascular Drugs in Patients Following Coronary Intervention; Analysis from the Registry Database with the 35-Year History
Authors: Hidetoshi Yasuda, Hiroshi Iwata, Takuma Koike, Yuichi Chikata, Takehiro Funamizu, Shinichiro Doi, Jun Shitara, Hirohisa Endo, Hideki Wada, Ryo Naito, Manabu Ogita, Tomotaka Dohi, Takatoshi Kasai, Shinya Okazaki, Katsumi Miyauchi, Hiroyuki Daida, Tohru Minamino
Journal: Circulation (2021)

Introduction: The evidence-based optimal medical therapy has been encouraged in the treatment of patients with coronary artery disease. However, as follow-up periods are limited (-5 years) in the most of randomized trials, prognostic efficacy of drugs in longer time period has not been fully evaluated. Therefore, this registry-based study aimed to simultaneously address the long-term prognostic impact of 6 major classes of cardiovascular (CV) drugs, beta-blockers (BBs), calcium channel blockers (CCBs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), Statins and Non-aspirin antiplatelets following percutaneous coronary intervention (PCI). Methods and Results: This is an analyses of single center prospective registry with lengthy history launched in 1984. Consecutive 6,299 patients underwent first PCI between 1984 and 2018 were included and CV mortality was set as the endpoint. Median and the range of follow-up period is 8.8, 0-28.9 years, respectively. Cox proportional hazard analyses adjusted by age, gender, BMI, diabetes and cardiac and renal function simultaneously evaluated the prognostic impacts of 6 major CV drugs in the entire population and patients with acute coronary syndrome (ACS). Among 6 drugs, ARBs (Hazard Ratio (HR): 0.72, 95% confidence interval (95% CI): 0.55-0.93, p=0.01), Non-aspirin antiplatelets (0.67, 0.53-0.86, p=0.002) and Statins (0.56, 0.44-0.7, p&lt;0.001) were significantly associated with reduced risk of CV mortality in the entire PCI population ( Figure A ). In ACS patients (n=1,790), only Statins at PCI predicted the reduced risk of CV mortality (HR: 0.44, 95%CI 0.28-0.68 p&lt;0.001) ( Figure B ). Conclusions: This long-term PCI registry-based analyses demonstrated the significant prognostic efficacy of ARBs, antiplatelets other than aspirin and statins. In ACS patients, only Statins, not other 5 classes of major CV drugs, were associated with reduced risk of CV mortality.
Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
Authors: Frank L. van de Veerdonk, Giorgia Renga, Marilena Pariano, Marina M. Bellet, Giuseppe Servillo, Francesca Fallarino, Antonella De Luca, Rossana G. Iannitti, Danilo Piobbico, Marco Gargaro, Giorgia Manni, Fiorella D’Onofrio, Claudia Stincardini, Luigi Sforna, Monica Borghi, Marilena Castelli, Stefania Pieroni, Vasileios Oikonomou, Valeria R. Villella, Matteo Puccetti, Stefano Giovagnoli, Roberta Galarini, Carolina Barola, Luigi Maiuri, Maria Agnese Della Fazia, Barbara Cellini, Vincenzo Nicola Talesa, Charles A. Dinarello, Claudio Costantini, Luigina Romani
Journal: Journal of Clinical Investigation (2021)

Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1-dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.
Abstract 12471: Bleeding Challenges in Pediatric Ventricular Assist Devices- A Study From the ACTION Registry
Authors: Neha Bansal, Muhammad Shezad, Matthew J O'Connor, Jonathan Edelson, Arene Butto, Scott R Auerbach, Jennifer Conway, Farhan Zafar, David N Rosenthal
Journal: Circulation (2021)

Background: Ventricular assist devices (VAD) are increasingly used in children with end-stage heart failure. Bleeding is a major complication of VAD, but most reports have focused on central nervous system (CNS) bleeding. Our objective was to determine the incidence &amp; consequences of non-CNS bleeding in pediatric VADs. Methods: We examined adverse events (AE) &amp; outcomes of all patients implanted with a VAD at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers between 9/2018-5/2021. Major bleeding event (MBE) was defined as an episode of suspected bleeding resulting in death, reoperation, hospitalization or blood transfusion (&gt;7days after implant). Variables were analyzed using chi square &amp; Mann Whitney test and outcomes were assessed by Kaplan Meier (KM) survival curves. Results: A total of 407 patients were prospectively enrolled in the ACTION registry, of which 82 (20.1%) had a MBE. The median duration of support was 72 days (range 6-1101). MBE was most common in paracorporeal continuous flow devices (42/82 devices, 51%). MBE was gastrointestinal in 30.3% &amp; thoracic in 38.5%. Patients with MBE were more likely to have congenital heart disease (CHD) or previous cardiac operation &amp; were less likely to have had VAD as a bridge to transplant (Table). Within 14 days post MBE, 31 subjects had another major AE (14 major infection, 13 another MBE, 2 stroke and 1 device malfunction). Unadjusted survival in patients with MBE was significantly worse than those without (p&lt;0.001) (Figure). Conclusion: MBE after VAD implant was seen in 20% of pediatric VAD patients, a higher proportion of whom had CHD. MBE was associated with other major AEs post-VAD and also with worse survival.
SURG-15. PITUITARY SPINDLE CELL ONCOCYTOMA: A CASE REPORT AND LITERATURE REVIEW
Authors: Taha Taka, Chen Yi Yang, Joshua Limbo, Alvin Chan, Jordan Davies, Edward Kuan, Scott Turner, Frank P K Hsu
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Spindle cell oncocytoma (SCO) of the pituitary gland is an extremely rare non-functional WHO grade 1 tumor. SCO are often misdiagnosed as nonfunctional pituitary adenomas on pre-operative imaging. They are often hypervascular and locally adherent, which increases hemorrhage risk and limits surgical resection, leading to increased risk of recurrence. We report a case of SCO treated at our institution and provide a review of the current literature. METHODS A 75-year-old male with a history of hypertension, left thalamic stroke, Parkinson’s disease, and normal pressure hypertension presented to neurosurgery clinic with bitemporal hemianopsia, hyponatremia, and abnormal gait and mobility. Imaging showed an enhancing intra- and suprasellar, hyperdense tumor mass measuring 3.0 cm in diameter. We performed a systemic literature search in the PubMed database to identify previous reports of spindle cell oncocytoma. After exclusion of studies that did not meet criteria, 32 publications were selected for critical reading. RESULTS The patient underwent an endoscopic transsphenoidal resection of the tumor via a multi-disciplinary team. The tumor was fibrous and adherent to the intrasellar dura, with gross invasion of the diaphragm sella, necessitating partial resection of the diaphragm. The defect was repaired, and the patient made an uncomplicated recovery. Post-operatively, the patient experienced improved vision. Upon literature review, SCO present in older adults with an average age of 56.2 ± 14.7 with visual deficits (67.9%), headache (33.3%), hypopituitarism (24.7%), and nausea (11.1%). Full resection was achieved in 38.6% of cases leading to recurrence rate of 23.5% with an average time until recurrence of 32.5 months (range 1-120 months). CONCLUSION Careful surgical technique is needed due to SCO hypervascularity and strong adherence to minimize risk of injury to surrounding neurovascular structures. Long-term follow up is recommended due risk of recurrence.
Abstract 1958: Age Related Changes in Left Atrial Hemodynamics in Normal Adults
Authors: Paul S Hees, Jon R Resar, Richard Ringel, Edward P Shapiro
Journal: Circulation (2007)

INTRODUCTION A marked shift in LV filling from early to late diastole occurs with normal aging and is often ascribed to changes in LV relaxation. Yet, left atrial properties also affect LV filling, and may also change with age, but have not been studied. We recorded atrial pressure-volume loops in patients with normal LV function over a wide age range undergoing percutaneous PFO closure after paradoxical embolism. METHODS We studied 35 adults undergoing cath for PFO closure (age range=24 – 81). Baseline LV diastolic function was measured by transmitral doppler echo and tissue doppler. Just before closure, a high-fidelity pressure sensor was placed across the PFO into the LA; in a subset of patients (n=18), a 2-sensor catheter was advanced transmitrally to record simultaneous LVP and LAP. In them, LV relaxation was estimated as τ by 3-parameter fit. Balloon inflation achieved IVC occlusion; LA area by transthoracic echo served as volume surrogate in P-V loops. Elastance at end-systole (Ees) and end-reservoir phase (Eer) are slopes from IVC occlusion loops (Figure ). RESULTS As expected, age was associated with rising peak A-wave velocity (p≤.001), and falling E/A (p≤.001) and tissue-doppler E/A (p≤.002). τ did not vary with age (r=.20, p=.43). At rest, age was associated with rising peak (p≤.05) and minimum (p≤.02) A-wave LAP, and a trend upward in mean LAP (p≤.07). Both Ees (p≤.01) and Eer (p≤.05) fell with age. CONCLUSIONS Atrial contractility declines with age, despite increasing late transmitral flow, suggesting increased preload. At the same time, reduced atrial elastance at onset of LV filling (end reservoir) may potentiate the shift to later filling with age.
Abstract 13684: The Function Of S100A8 In Human Primary Alveolar Epithelial Cells In Emphysema
Authors: Chih-ru Lin, Karim Bahmed, Gerard Criner, Nathaniel Marchetti, Sudhir Bolla, Beata Kosmider
Journal: Circulation (2021)

Pulmonary emphysema is characterized by the destruction of alveolar septa and impaired gas exchange. Cigarette smoking induces oxidative stress and is the main risk factor of lung injury and this disease development. There are limited therapeutic strategies for emphysema. Furthermore, cardiovascular diseases are the major cause of mortality in these patients. Alveolar type II (ATII) cells have stem cell potential to self-renew and regenerate the alveolar epithelium after damage. We isolated ATII cells from control nonsmoker and smoker organ donors and patients with emphysema to determine the nuclear role of S100A8. S100A8 is a small protein of 93 amino acids involved in cell growth and cytoprotection. We also used human alveolar epithelial A549 cells treated with cigarette smoke extract. Our results show increased oxidative stress as determined by 4-hydroxynonenal levels in A549 cells. We isolated cytoplasmic and nuclear fractions and observed that this exposure reduced S100A8 protein levels in the nucleus using Western blotting. This corresponded to our data using lung tissue and ATII cells obtained from smokers and emphysema patients. Moreover, we examined S100A8 nucleocytoplasmic shuttling and its stability using proteasome inhibitor and cycloheximide chase assay to determine protein function in the cytoplasm and nucleus in A549 cells. We immunoprecipitated S100A8 in A549 cells exposed to cigarette smoke and detected decreased S100A8 interaction with nuclear proteins by mass spectrometry analysis. We generated a stable A549 cell line with S100A8 knockout using the CRISPR/Cas9 strategy to determine its function. S100A8 ubiquitination and proteasomal degradation were also evaluated in human ATII cells isolated from control non-smokers, smokers, and emphysema. The findings improve our knowledge of the nuclear role of S100A8 in emphysema pathophysiology.
Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study
Authors: Saemundur Rognvaldsson, Elias Eythorsson, Sigrun Thorsteinsdottir, Brynjar Vidarsson, Pall Torfi Onundarson, Bjarni A. Agnarsson, Margret Sigurdardottir, Ingunn Thorsteinsdóttir, Isleifur Olafsson, Hrafnhildur L. Runolfsdottir, Dadi Helgason, Arna R. Emilsdottir, Arnar S. Agustsson, Aron H. Bjornsson, Gudrun Kristjansdottir, Asdis Rosa Thordardottir, Olafur Skuli Indridason, Asbjorn Jonsson, Gauti Kjartan Gislason, Andri Olafsson, Hlif Steingrimsdottir, Petros Kampanis, Malin Hultcrantz, Brian G. M. Durie, Stephen Harding, Ola Landgren, Runolfur Palsson, Thorvarður Jon Love, Sigurdur Yngvi Kristinsson
Journal: Blood Cancer Journal (2021)

Abstract Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81–1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52–1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.
Efficacy and safety of ustekinumab in Behçet disease: Results from the prospective phase 2 STELABEC trial
Authors: Jonathan London, Alexis Régent, Jérémie Dion, Léa Jilet, Marie Jachiet, Olivier Lidove, Fleur Cohen-Aubart, Selim Aractingi, Sarah Guégan, Jean-Loup Pennaforte, Hendy Abdoul, Xavier Puéchal, Benjamin Terrier
Journal: Journal of the American Academy of Dermatology (2021)
Pegcrisantaspase in Combination with Venetoclax for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: A Phase 1 Study
Authors: Sandrine Niyongere, Vu H. Duong, Dominique R Bollino, Rena G. Lapidus, Erin T. Strovel, Jinoos Zarrabi, Osman Mohamed Bah, Sunita Philip, Veronica Kflu, Maria R. Baer, Ashkan Emadi
Journal: Blood (2021)
Abstract P506: Sirt6 Overexpression Inhibits Senescence And Inflammation In Human Mesenchymal Stem Cells
Authors: Rahul Neupane, Darukeshwara Joladarashi, Keith Youker, Muthu Kumar Krishnamoorthi, Arvind Bhimaraj, Ashrith Guha, Rajarajan Amirthalingam Thandavarayan
Journal: Circulation Research (2021)

Background: Mesenchymal Stem Cells (MSCs) offer regenerative and therapeutic potential in an injured tissue in diabetic conditions. But the functional efficiency of MSCs has been shown to decrease with diabetes and aging. This reduces the potential of cell-based therapy in diabetic patients. Recent studies have established the role of sirtuin family proteins in metabolic disease, inflammation, longevity, and DNA repair. However, their potential to be used as a therapeutic target in cardiomyopathy and heart failure remain unexplored. Objective: To investigate the role of Sirtuin 6 (SIRT6) in mesenchymal stem cells senescence and cardiac regeneration. Methods and Results: We performed genomics and proteomics in the human control and diabetic heart tissues collected from the heart transplant. Human MSCs were treated with high glucose and mouse MSCs were derived from the bone marrow of diabetic db/db mice for this study. We found that SIRT6 expression is reduced in the myocardium of diabetic patients compared to non-diabetic controls. The SIRT6 expression decreased in high glucose-treated human MSCs compared to mannitol-treated control MSCs as well as in db/db mice MSCs compared to control mice MSCs. These high glucose-treated human MSCs and db/db mice MSCs showed increased expression of senescence and inflammation-related markers like that in diabetic human myocardium. Furthermore, we used small interfering RNA (SIRT6-siRNA) in human MSCs to knock down the SIRT6 gene and validated our findings. Indeed, the knockdown of SIRT6 promoted senescence and inflammation in those MSCs. Finally, we used adeno-associated viruses (AAV-SIRT6) to overexpress SIRT6 in MSCs treated with high glucose and performed proteomic analysis. SIRT6 overexpression in high glucose-treated MSCs reduced the expression of senescence and inflammation related genes and proteins. Conclusion: Our results highlight the importance of SIRT6 in diabetic myocardium and its role in balancing senescence and inflammation in MSCs. The validation of such in vitro studies in a diabetic mouse model ( db/db ) along with transplantation of SIRT6 overexpressed db/db MSCs into the myocardium of diabetic mice could open doors to successfully use MSC therapy in diabetic patients in the future.
Abstract 14369: Smooth Muscle Specific Deletion of RSK2 Suppresses Vasoconstriction of Resistance Arteries
Authors: Ramon J Ayon, Jaspreet K Kalara, Swapnil K Sonkusare, Avril V Somlyo
Journal: Circulation (2021)

Introduction: Intracellular Ca 2+ is a vital second messenger that plays a fundamental role in regulating intraluminal pressure- and agonist-induced vasoconstriction. Our laboratory previously demonstrated that intraluminal pressure and G-protein coupled receptor agonist stimulation activate p90 ribosomal S6 kinase 2 (RSK2). RSK2, in turn, phosphorylates the regulatory light chain of myosin (RLC 20 ) to induce constriction of small, resistance-sized arteries. More recently, we discovered that resistance arteries from global KO RSK2 mice exhibited a more dilated luminal diameter, reduced myogenic tone and RLC 20 phosphorylation, and decreased blood pressure. However, it is unclear whether the observed effects are a result of RSK2 global deletion in the mouse which may cause developmental abnormalities affecting the cardiovascular system. Hypothesis: We hypothesize that smooth muscle-specific RSK2 signaling in mouse resistance arteries is a significant regulator of myogenic tone and arterial stiffness. Methods: Inducible smooth muscle-specific KO mice for RSK2 (RSK2 SMC-/- ) were generated to study the role of RSK2 signaling in the regulation of vascular tone. Pressure myography studies assessed vascular reactivity in 4 th - and 5 th -order mesenteric arteries (MAs) isolated from RSK2 SMC-/- and RSK2 fl/fl mice. Results: The downregulation of normal RSK2 expression in resistance arteries was confirmed by Western blot. Our data shows that the intraluminal pressure-induced constriction of MAs is significantly attenuated in RSK2 SMC-/- mice (n=7 each group). Additionally, RSK2 SMC-/- resistance arteries experienced a delay in development of myogenic tone at 40 mmHg indicating that RSK2 signaling is sensitive to small changes in intraluminal pressure. Furthermore, MAs from RSK2 SMC-/- mice exhibited decreased vascular stiffness (indicated by enhanced strain, and rightward shift of stress-strain relationship) when compared to MAs from RSK2 fl/fl mice. Conclusions: This study provides novel evidence that smooth muscle RSK2 signaling contributes to pressure-induced vasoconstriction, and vascular stiffness. Inhibiting smooth muscle RSK2 activity may represent a novel strategy for rescuing vascular function in hypertensive patients.
CD19-CAR T Cells Develop Exhaustion Epigenetic Programs during a Clinical Response
Authors: Caitlin C. Zebley, Charmaine Brown, Tian Mi, Yiping Fan, Shanta Alli, Shannon Boi, Giovanni Galletti, Enrico Lugli, Deanna Langfitt, Jean-Yves Metais, Timothy Lockey, Michael M Meagher, Brandon M Triplett, Aimee C Talleur, Stephen Gottschalk, Benjamin Youngblood
Journal: Blood (2021)
Abstract 10933: Informal Caregivers’ Burden and Its Predictors in Heart Failure: A Mixed Methods Study
Authors: Angela Durante, Ahtisham Younas, angela cuoco, Valentina Zeffiro, Bridgette Brawner, Josiane Boyne, Raul Juarez-Vela, Ercole Vellone
Journal: Circulation (2021)

Introduction: Caring for relatives with heart failure is emotionally and physically intensive for informal caregivers leading to caregiver burden. Evidence also suggests that caregiver burden affects the quality of life of both components of the patient-caregiver dyad. Previous research provides a limited understanding of the nature of caregiver burden and its influencing factors from a dyadic perspective. Hypothesis: To develop a comprehensive understanding of caregiver burden, and to identify its predictors with a dyadic perspective Methods: A convergent mixed-method approach was used. In total, 184 patients with heart failure and their informal caregivers completed validated scales to measure burden, care dependency, quality of life, and social support and 50 caregivers participated also to a semi-structured interviews to better understand the caregiver experience. Multiple regression analysis was conducted to identify the predictors and qualitative content analysis was performed on qualitative data. The results were merged using joint displays. Results: Caregiver burden was predicted by patient worse cognitive impairment, lower physical quality of life, and a higher care dependency perceived by the caregivers. Qualitative and mixed analysis demonstrated that caregiver burden has a physical, emotional, and social nature. In particular time constraints, anticipated concerns about personal future, and generalized fatigue and exhaustion were significant predictors of caregiver burden, thereby affecting their caregiving. Conclusions: Caregiver burden can affect the capability of informal caregivers to support and care for their relatives with heart failure. There is a dire need for development and evaluation of individual and community-based strategies to address caregiver burden so as to enhance the quality of life of both caregivers and their relatives with heart failure.