tbuckley/cabot-search huggingface dataset:
Abrogation of IL-6-mediated JAK/STAT signaling by the cyclopentenone prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2 in oral squamous carcinoma cells
Authors: Hessam Siavash, Nikolaos G. Nikitakis, John J. Sauk
Journal: Cancer Research (2004)

4403  Antineoplastic effects of cyclopentenone prostaglandins, especially 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), have been reported in various types of cancer. In oral squamous cell carcinoma (SCC), we recently demonstrated that 15d-PGJ2 induces cell growth inhibition and apoptosis accompanied by downregulation of the oncogenic signal transducer and activator of transcription 3 (Stat3) signaling pathway. To investigate the mechanism underlying 15d-PGJ2-mediated repression of Stat3 in oral SCC, we assessed the effects of 15d-PGJ2 on upstream activators of Stat3, including the epidermal growth factor receptor (EGFR) and janus kinase (JAK)-mediated signaling pathways. Oral SCC cells were treated with interleukin 6 (IL-6), transforming growth factor alpha (TGF-α), 15d-PGJ2, 9,10-dihydro-15d-PGJ2, a 15d-PGJ2 analog with structural modifications lacking the reactive carbonyl group, or the specific JAK inhibitor AG490. Tyrosine phosphorylation of EGFR, JAKs, and Stat3, were assessed by immunoprecipitation and Western blot analyses. Treatment with 15d-PGJ2 abrogated IL-6-mediated Stat3 activation. In contrast, exogenous treatment with TGF-α reversed the inhibitory effects of 15d-PGJ2 on Stat3 signaling. Importantly, 15d-PGJ2 selectively inhibited constitutive and IL-6-mediated JAK phosphorylation without affecting EGFR activation. Moreover, 9,10-dihydro-15d-PGJ2 failed to inhibit JAK and Stat3 phosphorylation, suggesting that the repression of IL-6 mediated JAK/Stat3 signaling by 15d-PGJ2 requires the reactive α,β-unsaturated carbon within the cyclopentenone ring. Finally, AG490-mediated inhibition of JAK signaling also resulted in significant cell growth inhibition and apoptosis. These findings provide the first evidence for downregulation of IL-6-mediated JAK/Stat3 signaling by cyclopentenone prostaglandin 15d-PGJ2 in cancer. These results further suggest that targeting of JAK signaling may represent a promising therapeutic approach in oral SCC. [Supported by PHS/NIH DE13118, DE12606 and DE014935]
In type 2 diabetes, some glucose-lowering drugs reduce HbA<sub>1c</sub> more than others; drugs do not differ for mortality
Authors: Gunjan Y. Gandhi
Journal: Annals of Internal Medicine (2020)

Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med. 2020;173:278-86. 32598218.
EUFOREA expert board meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: Definitions and management
Authors: Claus Bachert, Joe K. Han, Martin Wagenmann, Werner Hosemann, Stella E. Lee, Vibeke Backer, Joaquim Mullol, Philippe Gevaert, Ludger Klimek, Emanuel Prokopakis, Andrew Knill, Carlo Cavaliere, Claire Hopkins, Peter Hellings
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 14600: Pre-existing Autoimmune Disease and the Risk for Cardiovascular and Non-cardiovascular Immune Mediated Adverse Events With Immune Checkpoint Inhibitors
Authors: Charlotte Lee, Zsofia D Drobni, Amna Zafar, Raza M Alvi, Sean P Murphy, Ramya C Mosarla, Paula K Rambarat, Sarah B Hartmann, Hannah K Gilman, Leyre Zubiri, Vineet K Raghu, Ryan J Sullivan, Daniel A Zlotoff, Alexander Faje, Kerry L Reynolds, Tomas G Neilan
Journal: Circulation (2020)

Introduction: The use of immune checkpoint inhibitors (ICIs) is associated with an increase in cardiovascular events. The mechanism is likely related to immune activation and inflammation. Patients with pre-existing autoimmune disease have a baseline increased risk for cardiovascular disease and have been traditionally excluded from clinical trials of ICIs. There is limited data on the cardiovascular and non-cardiovascular safety of ICIs in these patients. Methods: This was a retrospective study of 2845 patients treated with an ICI at the Massachusetts General Hospital. This cohort was screened by individual chart review for patients with a diagnosis of an autoimmune disease prior to ICI therapy. These autoimmune patients were compared to controls at a 1:2 ratio. Baseline characteristics and risk of cardiovascular and non-cardiovascular immune related adverse events (iRAEs) were compared. Cardiovascular events were a composite of myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), stroke, transient ischemic attack (TIA), deep venous thrombosis (DVT), pulmonary embolism (PE), or myocarditis. Results: 93 patients had a diagnosis of an autoimmune disease prior to ICI. These patients were more likely to be older and to have a history of coronary artery disease, heart failure, chronic kidney disease, hypertension and diabetes mellitus. There were 12 events over a median follow-up period of 300 days. There was no significant difference in composite of cardiovascular events in follow-up (13 vs. 9.1%, autoimmune vs. none, P =0.41). The individual cardiovascular event rates were as follows: MI (4.3 vs. 0.5%, P =0.04), PCI (0 vs. 0.5%, P =1), CABG (0. vs. 0.5%, P =1), stroke (0 vs. 0%), TIA (0 vs. 0.5%, P =1), DVT (5.4 vs. 2.2%, P =0.17), PE (1.1 vs. 4.8%, P =0.17), and myocarditis (2.2 vs. 1.1%, P =0.60). There was an increased rate of pneumonitis (14 vs. 4%, P &lt;0.001) and skin toxicity (16 vs. 0%, P &lt;0.001). Conclusions: Patients with pre-existing autoimmune disease treated with an ICI had a higher baseline cardiovascular risk but did not have a significant increase in cardiovascular events in an unadjusted analysis. These patients did, however, have an increased rate of pneumonitis and skin toxicity after ICI.
Abstract 12786: Antithrombotic Therapy After Transcatheter Aortic Valve Implantation in Patients With Concomitant Indications for Long-term Oral Anticoagulation: A Systemic Review and Meta-analysis
Authors: GonÃ§alo Costa, Lino Gonçalves, rogerio teixeira
Journal: Circulation (2020)

Background: Ischemic and bleeding complications after transcatheter aortic valve implantation (TAVI) remain prevalent and affect survival. Atrial fibrillation (AF) is common in patients undergoing TAVI and constitutes an indication for long-term oral anticoagulation (OAC). Current guidelines on antithrombotic treatment in patients who have an indication for OAC after TAVI are based on expert opinion and suggest the use of vitamin K antagonist (VKA) either alone or in combination with aspirin or clopidogrel. Purpose: To compare OAC (VKA or direct oral anticoagulant) versus OAC in combination with single antiplatelet therapy (SAPT), either aspirin or clopidogrel, as antithrombotic treatment following TAVI in patients with an indication for long-term OAC or the prevention of cerebrovascular events, bleeding events and all-cause mortality. Methods: We systematically searched PubMed, Embase and Cochrane databases, in April 2020, for both interventional or observational studies comparing OAC with OAC plus SAPT. Random-effects meta-analysis for OAC and OAC combined with SAPT were performed. Results: Four studies were included (three registry-based and one randomized clinical trial) providing a total of 1218 patients, and 69 pooled cerebrovascular events. There was no statistical difference between OAC and OAC plus SAPT for the prevention of cerebrovascular events after TAVI (pooled OR 0.89 [0.51, 1.55], P=0.69, I 2 = 0%) - Figure. Similarly, there was a similar rate of all-cause mortality (pooled OR 0.98 [0.72, 1.35], P=0.91, I 2 = 0%). Furthermore, the rate of major bleeding or life-threatening events was significantly lower for OAC compared with the combined therapy (pooled OR 0.45 [0.29, 0.70], P&lt;0.01, I 2 = 5%). Conclusions: Our pooled data suggests that for patients with indication for long-term oral anticoagulation after TAVI, the routine use of double anti-thrombotic therapy (SAPT+OAC) compared to the use of OAC, conferred an increased risk of bleeding
Experimental infection of chmpanzees with genetically engineered S-gene mutants of Hepatitis B Virus
Authors: Saleen Kamili, Saleem Kamili, Aufra Araujo, Jonny Yokosawa, Stephan Locarinini, Christian Trautwein, John Spelbring, Howard Fields, Krzysztof Krawczynski
Journal: Hepatology (2002)
Abstract 14447: 1-year Mortality After ICD Implantation in Ischemic Heart Disease
Authors: Sebastian Ingelaere, Ruben Hoffmann, Yves R Vandekerckhove, Johan Vijgen, Jean-Benoît le Polain de Waroux, Georges Mairesse, Ivan Blankoff, Rik Willems
Journal: Circulation (2020)

Introduction: According to guidelines ICD implantation should not be performed in patients with an expected survival less than 1 year. We investigated how useful validated risk scores are to predict 1-y mortality after ICD implantation in patients with ischemic heart disease (IHD). Methods: The QERMID-ICD registry, managed by the Belgian health authorities, contains data of all patients implanted with an ICD. Participation is mandatory for reimbursement. We analyzed all new implantations between 01/02/2010 and 31/01/2018 in Belgian IHD patients. Data is available about age, gender, ejection fraction (EF), NYHA class, type of prevention, type of device, QRS duration, center volume, comorbidities and socio-economic status based on the area of residency. We performed a Cox proportional hazard regression and applied a modified version of the MADIT- (Goldenberg et al., JACC 2008) risk score (reported renal failure instead of BUN &gt; 26mg%) and AAACC (Nevzorov et al., JCE 2018) risk score (no data on anemia, so AACC score) to predict 1-y mortality. Results: On a total of 6320 IHD patients, the 1-y mortality was 5.7%. Patients who died within 1 year were significantly older (70.9 vs 65.9 years), had a worse EF (28.7 vs 31.5%) and differed in most comorbidities. In the Cox model age, worse EF, secondary prevention, VVI/DDD devices, atrial fibrillation, COPD, neurological antecedents and renal failure were independent predictors of 1-y mortality (table 1). Area under ROC was comparable for the modified Goldenberg and AACC score (0.647 vs 0.652). With a cut-off of 5 on the modified Goldenberg and 7 on the AACC-score a positive predictive value (PPV) of respectively 15.5% an 17.4% and negative predictive value of 94.2% and 94.7% were obtained. Conclusion: Despite significant differences in baseline characteristics, selection of patients not suitable for ICD implantation (because of high 1-y mortality risk) can only be slightly improved by using simple risk scores due to their low PPV.
Advances in 3D bioprinting technology for cardiac tissue engineering and regeneration
Authors: Nanbo Liu, Xing Ye, Bin Yao, Mingyi Zhao, Peng Wu, Guihuan Liu, Donglin Zhuang, Haodong Jiang, Xiaowei Chen, Yinru He, Sha Huang, Ping Zhu
Journal: Bioactive Materials (2020)

Cardiovascular disease is still one of the leading causes of death in the world, and heart transplantation is the current major treatment for end-stage cardiovascular diseases. However, because of the shortage of heart donors, new sources of cardiac regenerative medicine are greatly needed. The prominent development of tissue engineering using bioactive materials has creatively laid a direct promising foundation. Whereas, how to precisely pattern a cardiac structure with complete biological function still requires technological breakthroughs. Recently, the emerging three-dimensional (3D) bioprinting technology for tissue engineering has shown great advantages in generating micro-scale cardiac tissues, which has established its impressive potential as a novel foundation for cardiovascular regeneration. Whether 3D bioprinted hearts can replace traditional heart transplantation as a novel strategy for treating cardiovascular diseases in the future is a frontier issue. In this review article, we emphasize the current knowledge and future perspectives regarding available bioinks, bioprinting strategies and the latest outcome progress in cardiac 3D bioprinting to move this promising medical approach towards potential clinical implementation.
Abstract 15940: Wall Shear Stress and Vorticity in Atrial Fibrillation, Pulmonary Hypertension, and Normal Atrial Anatomy Models
Authors: David R Rutkowski, Alexey Glukhov, Alejandro Roldán-Alzate
Journal: Circulation (2020)

Introduction: Atrial fibrillation (AF) is a common cardiac rhythm disorder that is often comorbid with pulmonary hypertension (PH) and other conditions associated with abnormal atrial pressure and/or volume overload. In the setting of atrial dilation, mechanoelectric feedback has been linked to the development of ectopic beats that trigger paroxysmal AF mainly originating from pulmonary veins (PVs). However, the precise mechanisms remain poorly understood. Here, we aimed to characterize atrial wall shear stress (WSS) and vorticity in the left atrium of AF, healthy, and at-risk for AF (PH) patient models to develop predictors of AF risk. Methods: Magnetic resonance imaging and computed tomography data (10 AF, 10 PH, and 10 healthy volunteers) were obtained retrospectively. The left atria were manually segmented from each data set. Four-dimensional flow MRI was performed on one patient to derive PV flow data. The 30 atrial geometries and PV flow conditions were used to run numerical blood flow simulations, and atrial WSS and blood flow vorticity were analyzed. Results: As seen in Figure 1, wall shear stress was highest near the PV roots and on the posterior atrial wall, the most common sources of AF triggers. Average WSS and vorticity were significantly lower in PH patients than in both the healthy (p=0.003(WSS), p=0.011(vorticity)) and AF (p=0.046(WSS), p=0.069(vorticity)) groups. Both WSS (r=-0.66) and vorticity (r=-0.68) were moderately correlated to atrial volume in the PH group. Atrial volume was significantly larger in PH (p&lt;0.001) and AF (p&lt;0.001) groups than in the healthy group. Conclusions: The larger atrial volumes of PH and AF patients lead to altered flow profiles and less frequently flow jet impingement on the atrial wall models, leading to abnormal vorticity and WSS profiles. These long term flow abnormalities may influence the development and/or localization of electrical abnormalities and AF; although further study is needed to confirm this hypothesis.
Long-term instability of the intestinal microbiome is associated with metabolic liver disease, low microbiota diversity, diabetes mellitus and impaired exocrine pancreatic function
Authors: Fabian Frost, Tim Kacprowski, Malte Rühlemann, Maik Pietzner, Corinna Bang, Andre Franke, Matthias Nauck, Uwe Völker, Henry Völzke, Marcus Dörr, Jan Baumbach, Matthias Sendler, Christian Schulz, Julia Mayerle, Frank U Weiss, Georg Homuth, Markus M Lerch
Journal: Gut (2020)

The intestinal microbiome affects the prevalence and pathophysiology of a variety of diseases ranging from inflammation to cancer. A reduced taxonomic or functional diversity of the microbiome was often observed in association with poorer health outcomes or disease in general. Conversely, factors or manifest diseases that determine the long-term stability or instability of the microbiome are largely unknown. We aimed to identify disease-relevant phenotypes associated with faecal microbiota (in-)stability.A total of 2564 paired faecal samples from 1282 participants of the population-based Study of Health in Pomerania (SHIP) were collected at a 5-year (median) interval and microbiota profiles determined by 16S rRNA gene sequencing. The changes in faecal microbiota over time were associated with highly standardised and comprehensive phenotypic data to determine factors related to microbiota (in-)stability.The overall microbiome landscape remained remarkably stable over time. The greatest microbiome instability was associated with factors contributing to metabolic syndrome such as fatty liver disease and diabetes mellitus. These, in turn, were associated with an increase in facultative pathogens such as Enterobacteriaceae or Escherichia/Shigella. Greatest stability of the microbiome was determined by higher initial alpha diversity, female sex, high household income and preserved exocrine pancreatic function. Participants who newly developed fatty liver disease or diabetes during the 5-year follow-up already displayed significant microbiota changes at study entry when the diseases were absent.This study identifies distinct components of metabolic liver disease to be associated with instability of the intestinal microbiome, increased abundance of facultative pathogens and thus greater susceptibility toward dysbiosis-associated diseases.
Abstract 14216: Predictors of 30-day and 1-year Mortality After Transvenous Lead Extraction for Device Infection
Authors: Kay Khine, Ashwani Gupta, Heath E Saltzman, Steven Kutalek
Journal: Circulation (2020)

Introduction: The incidence of device infection is constantly increasing; requiring transvenous lead extraction (TLE). Data regarding predictors of short and long-term mortality after TLE for infection are limited. Methods: We collected data regarding 30-day and 1-year mortality of patients undergoing TLE at a university hospital between April 2004 and June 2015. Patients with less than 30-day follow up were excluded. Results: Out of total 1223 TLE procedures, 700 were performed for infectious indications. 30-day follow-up was available for 620 patients (88.6%) and 1-year follow up was available for 541 patients (77.3%). Overall 30-day mortality was 9% (4.3% for pocket infection, 12.3% for systemic infection) and 1-year mortality was 27.5% (16% for pocket infection, 35.8% for systemic infection). Patient age, end-stage renal disease, history of valve replacement, atrial fibrillation, Staphylococcus aureus infection, systemic infection, any procedural complication, elevated WBC count, low hemoglobin, need for CCU admission, need for pressor support, acute kidney injury, cardiogenic shock and need for blood transfusion were predictors of both 30-day and 1-year mortality in univariate analysis. Any retained fragment was predictor of 30-day mortality. Peripheral vascular disease and low platelet count were predictors of 1-year mortality. Patient age, history of valve replacement, need for pressor support and low hemoglobin were independent predictors of 30-day as well as 1-year mortality in multivariate analysis. End-stage renal disease, atrial fibrillation, elevated WBC count and need for CCU admission were independent predictors of 30-day mortality. Systemic infection, low platelet count and need for blood transfusion were predictors of 1-year mortality. Strongest predictor of 30-day mortality was history of valve replacement (Odds ratio 4.23) and strongest predictor of 1-year mortality was need for pressor support (Odds ratio 3.12). Conclusions: In conclusion, 30-day and 1-year mortality after device infection remains high despite successful TLE. Patient age, history of valve replacement, need for pressor support and low hemoglobin are independent predictors of both short and long-term mortality in multivariate analysis.
Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF
Authors: Yan Deng, Maodi Xie, Qian Li, Xuewen Xu, Wei Ou, Yabing Zhang, Haitao Xiao, Hai Yu, Yanyi Zheng, Yu Liang, Chunling Jiang, Guo Chen, Dan Du, Wen Zheng, Shisheng Wang, Meng Gong, Yaohui Chen, Rong Tian, Tao Li
Journal: Circulation Research (2020)

Rationale: Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction. Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. Objective: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model. Methods and Results: By combining the age, long-term high-fat diet, and desoxycorticosterone pivalate challenge in a mouse model, we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of IL (interleukin)-1β/IL-18 and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokine–triggered mitochondrial dysfunction and fibrosis. Moreover, β-hydroxybutyrate downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of CS (citrate synthase) and inhibition of fatty acid uptake. Conclusions: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis, which can be ameliorated by promoting β-hydroxybutyrate abundance.
Vi-specific serological correlates of protection for typhoid fever
Authors: Celina Jin, Jennifer Hill, Bronwyn M. Gunn, Wen-Han Yu, Lindsay C. Dahora, Elizabeth Jones, Mari Johnson, Malick M. Gibani, Rachel L. Spreng, S. Munir Alam, Anna Nebykova, Helene B. Juel, S. Moses Dennison, Kelly E. Seaton, Jonathan K. Fallon, Georgia D. Tomaras, Galit Alter, Andrew J. Pollard
Journal: The Journal of Experimental Medicine (2020)

Typhoid Vi vaccines have been shown to be efficacious in children living in endemic regions; however, a widely accepted correlate of protection remains to be established. We applied a systems serology approach to identify Vi-specific serological correlates of protection using samples obtained from participants enrolled in an experimental controlled human infection study. Participants were vaccinated with Vi-tetanus toxoid conjugate (Vi-TT) or unconjugated Vi-polysaccharide (Vi-PS) vaccines and were subsequently challenged with Salmonella Typhi bacteria. Multivariate analyses identified distinct protective signatures for Vi-TT and Vi-PS vaccines in addition to shared features that predicted protection across both groups. Vi IgA quantity and avidity correlated with protection from S. Typhi infection, whereas higher fold increases in Vi IgG responses were associated with reduced disease severity. Targeted antibody-mediated functional responses, particularly neutrophil phagocytosis, were also identified as important components of the protective signature. These humoral markers could be used to evaluate and develop efficacious Vi-conjugate vaccines and assist with accelerating vaccine availability to typhoid-endemic regions.