tbuckley/cabot-search huggingface dataset:
Abstract 593: A Novel PGE2 Receptor 4-Selective Agonist Suppresses Acute Rejection via Inflammatory Factor Regulation in Murine Cardiac Allografts
Authors: Masahito Ogawa, Jun-ichi Suzuki, Kiyoshi Takayama, Mitsuaki Isobe
Journal: Circulation (2006)

Background: PGE2 exerts an anti-inflammatory action by ligation of the PGE2 receptor subtype EP4 among the four of the receptor subtypes in inflammatory diseases. Because little is known about the effect of EP4R in transplantation, we examined the anti-inflammatory effect of EP4 using the murine cardiac transplantation model. Methods and Results: We developed a novel EP4 selective agonist, EP4RAG, and performed subcutaneous injection of EP4RAG (3mg/kg) into recipient mice. We demonstrated that EP4RAG treatment prolonged graft survival (13.5+/−1.4 days, P&lt;0.05, n=7) compared to that of the vehicle treated group (7.3+/−0.2 days, n=7). Allografts were harvested on day 7 for pathological and molecular examination. While the vehicle treated group showed severe myocardial cell infiltrations (38.4+/−2.5 %, n=10), the EP4RAG treated group attenuated the development (16.7+/−3.4 %, P&lt;0.05, n=8). EP4RAG suppressed various inflammatory factors such as cytokines (e.g. IFN-g, IL-6), chemokines (e.g. IP-10, MIP-1) and adhesion molecules (e.g. ICAM-1) compared to the vehicle treated group in mRNA and protein levels. In vitro assay, we demonstrated that EP4RAG suppressed T lymphocyte proliferation (0.067+/−0.001 OD, P&lt;0.05) compared to the control group (0.105+/−0.003 OD) by MLR. We also showed that EP4 mainly attenuated the activation of macrophages by co-culture. EP4RAG inhibited the activation of NF-kB compared to the control group in macrophages with IL-1beta stimulation. Conclusions: An EP4R agonist, EP4RAG is potent for the suppression of acute rejection through proinflammatory factor regulation.
ARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte function
Authors: Divij Mathew, Kimberly N. Kremer, Raul M. Torres
Journal: Journal of Clinical Investigation (2019)

Primary antibody deficiencies are the most common immunodeficiencies in humans; however, identification of the underlying genetic and biochemical basis for these diseases is often difficult, given that these deficiencies typically involve complex genetic etiologies. In this issue of the JCI, Bouafia et al. performed whole-exome sequencing on a pair of siblings with primary antibody deficiencies and identified genetic mutations that result in a deficiency of ARHGEF1, a hematopoietic intracellular signaling molecule that transmits signals from GPCRs. ARHGEF1-deficient lymphocytes from the affected siblings exhibited important functional deficits that indicate that loss of ARHGEF1 accounts for the observed primary antibody deficiency, which manifests in an inability to mount antibody responses to vaccines and pathogens. Thus, this report demonstrates an important role for ARHGEF1 in GPCR signal transduction required for appropriate adaptive immune responses in humans.
Relationship Between the Location of Eosinophils in the Airway Wall, Type-2 Gene Expression, and Airway Hyperresponsiveness in Asthma
Authors: Taha Al-Shaikhly, Andrew R. Parker, Ying Lai, James D. Nolin, Matthew C. Altman, Megan Larmore, Charles W. Frevert, Teal Hallstrand
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 031: Socioeconomic Trajectories Across the Life Course and Risk of All-cause and Cardiovascular Mortality: Prospective Findings From the Moli-sani Study
Authors: Marialaura Bonaccio, Augusto Di Castelnuovo, Simona Costanzo, Mariarosaria Persichillo, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello
Journal: Circulation (2018)

Introduction: A life course approach has been suggested as the most appropriated to establish the actual impact of socioeconomic status (SES) on health outcomes. Hypothesis: We assessed the hypothesis that SES trajectories from childhood to adulthood are useful to better evaluate the role of SES towards mortality risk in a large general population-based cohort. Methods: Longitudinal analysis on 22,194 subjects recruited in the general population of the Moli-sani study, Italy (2005-2010). Educational attainment (low/high) and SES in adulthood (measured by a score including occupational social class, housing and overcrowding, and dichotomized as low/high) were used to define four possible trajectories both in low and high SES in childhood (age of 8). Hazard ratios (HR) with 95% confidence intervals (95%CI) were calculated by multivariable Cox regression and competing risk models. Results: Over a median follow-up of 8.3 years (182,924 person-years), 1155 all-cause, of which 414 cardiovascular (CVD), deaths were ascertained. In the group with low SES in childhood, as opposed to those stably low (low education and low SES in adulthood), an upward in both educational attainment and material factors in adulthood was associated with lower risk of both all-cause (HR=0.64; 95%CI 0.52-0.79; Table) and CVD mortality (HR=0.62; 0.43-0.88), respectively. Subjects with high childhood SES experienced an increased risk of total and CVD death in absence of higher educational attainment despite a higher SES in adulthood (HR=1.47; 1.04-2.07 and HR=1.75;1.00-3.05, respectively) as compared to the group with both high education and high SES in adulthood. Conclusions: In conclusion, for individuals with low SES in childhood, an upward of both educational attainment and material factors over the life course is associated with lower risk of total and CVD death. In advantaged groups in childhood, lack of a higher educational attainment, rather than material factors, over the life course appears to be unfavourably associated with survival.
Outcomes of Relapsed/Refractory Patients with IDH1/2 Mutated AML Treated with Non-Targeted Therapy: Results from the NCRI AML Trials
Authors: Robert K. Hills, Rosemary Gale, David C. Linch, Brian J.P Huntly, Elli Papaemmanuil, Paresh Vyas, Alan K. Burnett, Nigel H. Russell
Journal: Blood (2018)
Detection and Differential Diagnosis of Prekallikrein Deficiency: Genetic Study of New Families and Systematic Review of the Literature
Authors: Stefano Barco, Stefanie Sollfrank, Alice Trinchero, Luigi Tomao, Barbara Zieger, Johanna A. Kremer Hovinga, Laura Conti, Anke Adenäuer, Erwin Miloni, Karl J. Lackner, Heidi Rossmann, Bernhard Lammle
Journal: Blood (2018)
Abstract 14631: Pulmonary Artery Calcification: A New Threat in Pulmonary Arterial Hypertension
Authors: Sophie Chabot, Grégoire Ruffenach, Virginie F Tanguay, François Potus, Steeve Provencher, Sébastien Bonnet
Journal: Circulation (2015)

Background: Pulmonary arterial hypertension (PAH) is associated with imbalance between proliferation and apoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs). Recently, we uncovered a role for microRNA-204 (miR-204), whose downregulation sustains the phenotype in time. In systemic vascular disease, miR-204 downregulation increases the Runt-related transcription factor 2 (RUNX2), a key osteogenic factor inducing calcification. The fact that PAH patients live longer increases the odds of developing PA calcification lesions. Interestingly, the presence and development of calcified lesions in PAH have not been explored. We thus hypothesized that miR-204-dependent upregulation of RUNX2 triggers the development of proliferative and calcified vascular lesions within the lungs, thus worsening PAH. Methods/Results: Using CT-scan, we showed that PAH patients (n=50; p&lt;0.05) had significant increase in distal PA calcification compared to control patients matched for age, sex and comorbidities known to promote vascular calcification. This non-invasive finding was histologically confirmed in the same patients post lung transplantation using Von Kossa staining (n=10; p&lt;0.05). Finally, increase in calcification contributes to worsening of PA compliance and is associated with poorer PAH patients’ survival (n=50; p&lt;0.05). At the molecular level, enhanced calcification in PAH patients correlates (n=43; p&lt;0.05) with a miR-204-dependent up regulation of RUNX2 in lungs, distal PA and primary cultured PASMCs (n=12-40, fold change ≈ 2.5). Using gain and loss of function approaches, we demonstrated in PASMCs from PAH and healthy donors (using siRNA and adenoviruses respectively) that RUNX2, promotes PAH-PASMC proliferation (Ki67), resistance to apoptosis (Annexin-V) and calcification (Alizarin red) (p&lt;0.05). Finally, in Sugen/hypoxia rat model of PAH, we demonstrated that RUNX2 inhibition improves pulmonary hemodynamic and reduces PA remodeling and calcification (n=5-12, p&lt;0.05). Conclusion: We demonstrated for the first time the presence of significant calcification in PAH distal PA contributing to PAH worsening and identified RUNX2 as an attractive new therapeutic strategy to improve PAH. *SC and GR equally contributed.
Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L‐PLUS 2)
Authors: Markus Peck‐Radosavljevic, Krzysztof Simon, Angelo Iacobellis, Tarek Hassanein, Zeid Kayali, Albert Tran, Mihaly Makara, Ziv Ben Ari, Marius Braun, Paul Mitrut, Sheng‐Shun Yang, Meral Akdogan, Mario Pirisi, Ajay Duggal, Toshimitsu Ochiai, Tomoko Motomiya, Takeshi Kano, Tsutae Nagata, Nezam Afdhal
Journal: Hepatology (2019)

Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small‐molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L‐PLUS 2 was a global, phase 3, randomized, double‐blind, placebo‐controlled study. Adults with CLD and baseline PCs &lt; 50 × 10 9 /L were randomized to receive once‐daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2‐7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 10 9 /L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint ( P &lt; 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 10 9 /L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) ( P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.
Resource-rational analysis: Understanding human cognition as the optimal use of limited computational resources
Authors: Falk Lieder, Thomas L. Griffiths
Journal: Behavioral and Brain Sciences (2019)

Abstract Modeling human cognition is challenging because there are infinitely many mechanisms that can generate any given observation. Some researchers address this by constraining the hypothesis space through assumptions about what the human mind can and cannot do, while others constrain it through principles of rationality and adaptation. Recent work in economics, psychology, neuroscience, and linguistics has begun to integrate both approaches by augmenting rational models with cognitive constraints, incorporating rational principles into cognitive architectures, and applying optimality principles to understanding neural representations. We identify the rational use of limited resources as a unifying principle underlying these diverse approaches, expressing it in a new cognitive modeling paradigm called resource-rational analysis . The integration of rational principles with realistic cognitive constraints makes resource-rational analysis a promising framework for reverse-engineering cognitive mechanisms and representations. It has already shed new light on the debate about human rationality and can be leveraged to revisit classic questions of cognitive psychology within a principled computational framework. We demonstrate that resource-rational models can reconcile the mind's most impressive cognitive skills with people's ostensive irrationality. Resource-rational analysis also provides a new way to connect psychological theory more deeply with artificial intelligence, economics, neuroscience, and linguistics.
Engineering Biomimetic Materials for Skeletal Muscle Repair and Regeneration
Authors: Karina H. Nakayama, Mahdis Shayan, Ngan F. Huang
Journal: Advanced Healthcare Materials (2019)

Although skeletal muscle is highly regenerative following injury or disease, endogenous self-regeneration is severely impaired in conditions of volume traumatic muscle loss. Consequently, tissue engineering approaches are a promising means to regenerate skeletal muscle. Biological scaffolds serve as not only structural support for the promotion of cellular ingrowth but also impart potent modulatory signaling cues that may be beneficial for tissue regeneration. In this work, the progress of tissue engineering approaches for skeletal muscle engineering and regeneration is overviewed, with a focus on the techniques to create biomimetic engineered tissue using extracellular cues. These factors include mechanical and electrical stimulation, geometric patterning, and delivery of growth factors or other bioactive molecules. The progress of evaluating the therapeutic efficacy of these approaches in preclinical models of muscle injury is further discussed.
Abstract 15653: Treatment With miRNA-101a Prevents Sustained Hypertension-induced Cardiac Fibrosis and Loss of Cardiac Function via Actions as an Endogenous Inhibitor of TGF-β Signaling
Authors: Yue Zhou, Thiam Chien Shiok, Arthur M Richards, Peipei Wang
Journal: Circulation (2017)

MiR-101a is a known tumor suppressor with recently reported anti-fibrotic effects, through c-FOS mediated TGF-β inhibition, in mouse myocardial infarction. We tested the efficacy of miR-101a mimic in treating transverse aortic constriction (TAC) induced cardiac fibrosis and investigated the anti-fibrotic mechanism. Method: Rat cardiac fibroblasts (cFB) were isolated to study miR-101a effects on cell proliferation (CCK8), collagen synthesis (sircol), cell apoptosis (Annexin V), and autophagy flux (bafilomycin A1). Potential targets in TGF-β signaling were screened by qPCR, WB and 3’UTR luciferase assay. After TAC, rats were given miR-101a mimics at 1, 3, 7-days (i.v. 1mg/kg) with assessments at 2 days and 2 & 12 weeks respectively. Fibrosis was determined by picro-sirius red staining. Left ventricle (LV) function was assessed by echocardiography and LV catheterization. Results: miR-101a inhibited cFB (1) activation evidenced by downregulation of α-SMA, collagen and fibronectin expression (2) proliferation ...
Ultrathin Bioresorbable Polymer Sirolimus-Eluting Stents Versus Thin Durable Polymer Everolimus-Eluting Stents
Authors: David E. Kandzari, Jacques J. Koolen, Gheorghe Doros, Joseph J. Massaro, Hector M. Garcia-Garcia, Johan Bennett, Ariel Roguin, Elie G. Gharib, Donald E. Cutlip, Ron Waksman
Journal: Journal of the American College of Cardiology (2018)

Coronary drug-eluting stent development has introduced new metal alloys, changes in stent architecture, and bioresorbable polymers. Whether these advancements improve long-term clinical safety and efficacy has been inconsistent in prior studies.The authors sought to compare late-term clinical outcomes among patients treated with an ultrathin strut (60 μm) bioresorbable polymer sirolimus-eluting stent (BP SES) and a thin strut (81 μm) durable polymer everolimus-eluting stent (DP EES) in a large randomized trial.BIOFLOW V (Biotronik Prospective Randomized Multicenter Study to Assess the Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in the Treatment of Subjects with Up to Three De Novo or Restenotic Coronary Artery Lesions V) was an international randomized trial comparing coronary revascularization with BP SES and DP EES regarding the primary endpoint of 12-month target lesion failure (TLF). Analysis of pre-specified 2-year clinical outcomes was performed.Among 1,334 patients randomized to treatment with BP SES (n = 884) or DP EES (n = 450), the 2-year TLF rate was 7.5% for BP SES and 11.9% for DP EES (-4.33% treatment difference; 95% confidence interval: -8.16% to -0.91%; p = 0.015), driven by differences in target vessel myocardial infarction (MI) (5.3% vs. 9.5%; p = 0.01) and ischemia-driven target lesion revascularization (2.6% vs. 4.9%; p = 0.04). Rates of cardiac death or MI were 7.0% versus 10.4% for BP SES and DP EES, respectively (p = 0.047). Late/very late definite stent thrombosis was statistically lower for BP SES compared with DP EES (0.1% vs. 1.0%; p = 0.045).In a large randomized trial, significant differences in both TLF and target vessel-related MI persisted through 2 years, favoring treatment with BP SES over DP EES. Significantly lower cumulative target lesion revascularization and late/very late stent thrombosis were also observed with BP SES. (Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in Subjects With Coronary Artery Lesions [BIOFLOW-V]; NCT02389946).
Abstract 352: Manf, a Structurally Unique Redox-sensitive Chaperone, Restores Er-protein Folding in the Ischemic Heart
Authors: Adrian Arrieta, Erik A Blackwood, Cathrine Aivati, Winston T Stauffer, Michelle Santo Domingo, Alina S Bilal, Anup V Sarakki, Donna J Thuerauf, Shirin Doroudgar, Christopher C Glembotski
Journal: Circulation Research (2018)

Rationale: In cardiomyocytes, secreted and membrane proteins critical for heart function are synthesized and folded in the sarcoplasmic/endoplasmic reticulum (SR/ER). We previously showed that myocardial ischemia decreases oxygen required for disulfide bond formation in nascent proteins, causing ER stress, i.e. the toxic accumulation of unfolded proteins, which contributes to cardiomyocyte death. In response to ER stress, the transcription factor ATF6 induces various ER-resident proteins that restore SR/ER protein folding, including ER chaperones. We found that ATF6 induces mesencephalic astrocyte-derived neurotrophic factor (MANF), a recently identified protein of unknown function. MANF is structurally unique, so its function could not be inferred by analogy to other proteins. Since we found that MANF is an ATF6-inducible ER-resident protein we hypothesized that it functions as a chaperone, and since MANF has 8 cysteine residues that are conserved in a wide range of species, that its chaperone function is redox-regulated and protective in the ischemic heart. Methods: The ability of recombinant MANF (rMANF) to suppress misfolded protein aggregation was examined in an in vitro chaperone assay. The effect of MANF knockdown on cell viability during simulated ischemia (sI) was determined in neonatal rat ventricular myocytes (NRVM). The effect of MANF loss-of-function in the ischemic heart, in vivo , was determined in a novel mouse model in which MANF is knocked down in cardiomyocytes. Results: rMANF formed disulfide-dependent complexes with and suppressed aggregation of model misfolded proteins in vitro , and these effects were lost when the cysteines in rMANF were mutated to alanine. In NRVM, MANF knockdown decreased viability during simulated ischemia; this viability deficit was restored upon ectopic expression of wild type, but not mutant MANF. MANF knockdown in the heart, in vivo , increased ischemia/reperfusion damage, and this damage was mitigated using an AAV9-based gene therapy approach to restore MANF expression. Conclusions: MANF is a novel redox-sensitive SR/ER-resident chaperone that is a critical contributor to SR/ER protein folding during the adaptive ER stress response and mitigates ischemia/reperfusion damage in the heart.
Association of fried food consumption with all cause, cardiovascular, and cancer mortality: prospective cohort study
Authors: Yangbo Sun, Buyun Liu, Linda G Snetselaar, Jennifer G Robinson, Robert B Wallace, Lindsay L Peterson, Wei Bao
Journal: BMJ (2019)

Abstract Objective To examine the prospective association of total and individual fried food consumption with all cause and cause specific mortality in women in the United States. Design Prospective cohort study. Setting Women’s Health Initiative conducted in 40 clinical centers in the US. Participants 106 966 postmenopausal women aged 50-79 at study entry who were enrolled between September 1993 and 1998 in the Women’s Health Initiative and followed until February 2017. Main outcome measures All cause mortality, cardiovascular mortality, and cancer mortality. Results 31 558 deaths occurred during 1 914 691 person years of follow-up. For total fried food consumption, when comparing at least one serving per day with no consumption, the multivariable adjusted hazard ratio was 1.08 (95% confidence interval 1.01 to 1.16) for all cause mortality and 1.08 (0.96 to 1.22) for cardiovascular mortality. When comparing at least one serving per week of fried chicken with no consumption, the hazard ratio was 1.13 (1.07 to 1.19) for all cause mortality and 1.12 (1.02 to 1.23) for cardiovascular mortality. For fried fish/shellfish, the corresponding hazard ratios were 1.07 (1.03 to 1.12) for all cause mortality and 1.13 (1.04 to 1.22) for cardiovascular mortality. Total or individual fried food consumption was not generally associated with cancer mortality. Conclusions Frequent consumption of fried foods, especially fried chicken and fried fish/shellfish, was associated with a higher risk of all cause and cardiovascular mortality in women in the US.
Abstract 20207: Lower Risk in Young Patients Aged < 50 With Atrial Fibrillation and Low CHA2DS2-VASc Risk Score
Authors: Laurent Fauchier, Arnaud Bisson, Nicolas Clementy, Denis Angoulvant, Dominique Babuty, Gregory Y Lip, Ben Freedman
Journal: Circulation (2017)

It is unclear whether oral anticoagulants (OAC) are beneficial for patients with atrial fibrillation (AF) at intermediate stroke risk i.e. CHA2DS2-VASc score of 1 (male) or 2 (female), and whether ...
Telomere length predicts for outcome to FCR chemotherapy in CLL
Authors: Kevin Norris, Peter Hillmen, Andrew Rawstron, Robert Hills, Duncan M. Baird, Christopher D. Fegan, Chris Pepper
Journal: Leukemia (2019)

We have previously shown that dividing patients with CLL into those with telomeres inside the fusogenic range (TL-IFR) and outside the fusogenic range (TL-OFR) is powerful prognostic tool. Here, we used a high-throughput version of the assay (HT-STELA) to establish whether telomere length could predict for outcome to fludarabine, cyclophosphamide, rituximab (FCR)-based treatment using samples collected from two concurrent phase II studies, ARCTIC and ADMIRE (n = 260). In univariate analysis, patients with TL-IFR had reduced progression-free survival (PFS) (P < 0.0001; HR = 2.17) and shorter overall survival (OS) (P = 0.0002; HR = 2.44). Bifurcation of the IGHV-mutated and unmutated subsets according to telomere length revealed that patients with TL-IFR in each subset had shorter PFS (HR = 4.35 and HR = 1.48, respectively) and shorter OS (HR = 3.81 and HR = 2.18, respectively). In addition, the OS of the TL-OFR and TL-IFR subsets were not significantly altered by IGHV mutation status (P = 0.61; HR = 1.24 and P = 0.41; HR = 1.47, respectively). In multivariate modeling, telomere length was the dominant co-variable for PFS (P = 0.0002; HR = 1.85) and OS (P = 0.05; HR = 1.61). Taken together, our data suggest that HT-STELA is a powerful predictor of outcome to FCR-based treatment and could be used to inform the design of future risk-adapted clinical trials.