Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model.

Roughly one-half of mice with partial defects in two immune tolerance pathways (AireLyn mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid-binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4 T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.

Thrombotic risk in patients with acute coronary syndromes discharged on prasugrel or clopidogrel: results from the PROMETHEUS study.

Aims: Based on recent clinical data, the 2020 ESC guidelines on non-ST-elevation acute coronary syndrome (NSTE-ACS) suggest to tailor antithrombotic strategy on individual thrombotic risk. Nonetheless, prevalence and prognostic impact of the high thrombotic risk (HTR) criteria proposed are yet to be described. In this analysis from the PROMETHEUS registry, we assessed prevalence and prognostic impact of HTR, defined according to the 2020 ESC NSTE-ACS guidelines, and if the benefits associated with prasugrel vs.

Chewed Versus Swallowed Ticagrelor in P2Y12 Inhibitor-Naïve Patients Undergoing Percutaneous Coronary Intervention.

Purpose: Dual antiplatelet therapy is standard for patients undergoing percutaneous coronary intervention (PCI) with stents. Traditionally, patients swallow the loading dose of a P2Y12 inhibitor before or during PCI. Time to achieve adequate platelet inhibition after swallowing the loading dose varies significantly.

Antithrombotic strategy variability in atrial fibrillation and obstructive coronary disease revascularised with percutaneous coronary intervention: primary results from the AVIATOR 2 international registry.

Background: Managing percutaneous coronary intervention (PCI) patients with atrial fibrillation (AF) presents challenges given that there are several potential antithrombotic therapy (ATT) strategies.

Aims: We examined ATT patterns, agreement between subjective physician ratings and validated risk scores, physician-patient perceptions influencing ATT and 1-year outcomes.

Methods: The AVIATOR 2 prospective registry enrolled 514 non-valvular AF-PCI patients from 11 sites.

Insights From Modern Imaging and Catheter Wire Measurements in Patients Undergoing Transcatheter Aortic Valve Replacement.

Background: Prior studies have neither described methods for crossing a severely stenotic aortic valve (AV) in light of modern imaging modalities (echocardiography, computed tomography, fluoroscopy) nor characterized a successful crossing. This study aimed to fill that gap.

Methods: Time to cross the valve (TTCV) was measured prospectively in 35 consecutive patients undergoing transcatheter AV replacement and used to define two groups (≤60 seconds or >60 seconds).

Prasugrel use and clinical outcomes by age among patients undergoing PCI for acute coronary syndrome: from the PROMETHEUS study.

Background: Prasugrel is a potent thienopyridine that may be preferentially used in younger patients with lower bleeding risk.

Objective: We compared prasugrel use and outcomes by age from the PROMETHEUS study. We also assessed age-related trends in treatment effects with prasugrel versus clopidogrel.

Antigen Complexed with a TLR9 Agonist Bolsters c-Myc and mTORC1 Activity in Germinal Center B Lymphocytes.

The germinal center (GC) is the anatomical site where humoral immunity evolves. B cells undergo cycles of proliferation and selection to produce high-affinity Abs against Ag. Direct linkage of a TLR9 agonist (CpG) to a T-dependent Ag increases the number of GC B cells.

Incidence, predictors and impact of stroke on mortality among patients with acute coronary syndromes following percutaneous coronary intervention-Results from the PROMETHEUS registry.

Background: Stroke represents a potentially calamitous complication among patients with acute coronary syndrome (ACS) undergoing percutaneous intervention (PCI). Data on the distribution of stroke occurrence post-PCI and its impact on mortality are scarce.

Objectives: We sought to determine the incidence, predictors and impact of stroke on mortality in ACS patients undergoing PCI.

Associations between use of prasugrel vs clopidogrel and outcomes by type of acute coronary syndrome: an analysis from the PROMETHEUS registry.

We sought to investigate the utilization of prasugrel and its association with outcomes relative to clopidogrel in three typical subgroups of ACS in a real-world setting. Prasugrel is superior to clopidogrel for reducing risk of ischemic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), but is associated with an increased risk of bleeding complications. PROMETHEUS was a retrospective multicenter observational study of 19,913 ACS patients undergoing PCI from 8 centers in the United States between 2010 and 2013.

Use of prasugrel and clinical outcomes in African-American patients treated with percutaneous coronary intervention for acute coronary syndromes.

Objective: To investigate the use of prasugrel after percutaneous coronary intervention (PCI) in African American (AA) patients presenting with acute coronary syndrome (ACS).

Background: AA patients are at higher risk for adverse cardiovascular outcomes after PCI and may derive greater benefit from the use of potent antiplatelet therapy.

Methods: Using the multicenter PROMETHEUS observational registry of ACS patients treated with PCI, we grouped patients by self-reported AA or other races.

Use of prasugrel vs clopidogrel and outcomes in patients with and without diabetes mellitus presenting with acute coronary syndrome undergoing percutaneous coronary intervention.

Background: Clinical trial data studies suggest superiority of prasugrel over clopidogrel in patients with diabetes. However, the use, safety and efficacy profile of prasugrel in unselected diabetic patients presenting with acute coronary syndromes (ACS) remain unclear.

Methods: PROMETHEUS was a prospective multicenter observational study of 19,919 ACS PCI patients enrolled between 2010 and 2013.

The prevalence, predictors and outcomes of guideline-directed medical therapy in patients with acute myocardial infarction undergoing PCI, an analysis from the PROMETHEUS registry.

Objectives: To investigate the prevalence, predictors and associations between guideline-directed medical therapy (GDMT) and clinical outcomes in acute myocardial infarction (AMI) patients undergoing percutaneous coronary intervention (PCI) from eight academic centers in the United States.

Background: Evidence for GDMT in patients with AMI comes from randomized controlled trials. The use of GDMT in clinical practice is unknown in this setting.

Simvastatin reduces TGF-β1-induced SMAD2/3-dependent human ventricular fibroblasts differentiation: Role of protein phosphatase activation.

Background: Excessive cardiac fibrosis due to maladaptive remodeling leads to progression of cardiac dysfunction and is modulated by TGF-β1-activated intracellular phospho-SMAD signaling effectors and transcription regulators. SMAD2/3 phosphorylation, regulated by protein-phosphatases, has been studied in different cell types, but its role in human ventricular fibroblasts (hVFs) is not defined as a target to reduce cytokine-mediated excessive fibrotic response and adverse cardiac remodeling. Statins are a class of drugs reported to reduce cardiac fibrosis, although underlying mechanisms are not completely understood.

Understanding the Musical Dance of the Engaged Coronary Catheter: Insights From Advanced Myocardial Mechanics.

A case of a 56-year-old woman with normal coronaries displays the side-to-side motion of the unengaged catheter followed by the rhythmic up-and-down, piston-like movements of the catheter tip after engagement.

Multilayer Control of B Cell Activation by the B Cell Antigen Receptor: Following Themes Initiated With Bill Paul.

This article describes the work I did in Bill Paul's lab as a postdoctoral fellow between 1979 and 1983, and to a lesser extent puts that work in the context of other work on B cell activation and antibody responses that was going on in Bill's lab at that time and shortly beforehand, including the discovery of interleukin 4. In addition, this work describes the subsequent and continuing work in my own lab following-up on themes I began during my time working directly with Bill. A particular emphasis was on understanding the biochemical mechanisms of signaling by the B cell antigen receptor (BCR) to the interior of the B cell.

Associations Between Complex PCI and Prasugrel or Clopidogrel Use in Patients With Acute Coronary Syndrome Who Undergo PCI: From the PROMETHEUS Study.

Background: Potent P2Y inhibitors might offer enhanced benefit against thrombotic events in complex percutaneous coronary intervention (PCI). We examined prasugrel use and outcomes according to PCI complexity, as well as analyzing treatment effects according to thienopyridine type.

Methods: PROMETHEUS was a multicentre observational study that compared clopidogrel vs prasugrel in acute coronary syndrome patients who underwent PCI (n = 19,914).

B Cell-Intrinsic MyD88 Signaling Promotes Initial Cell Proliferation and Differentiation To Enhance the Germinal Center Response to a Virus-like Particle.

Although TLR signaling in B cells has been implicated in the germinal center (GC) responses during viral infections and autoimmune diseases, the underlying mechanism is unclear. Bacterial phage Qβ-derived virus-like particle (Qβ-VLP) contains TLR ligands, which can enhance Qβ-VLP-induced Ab response, including GC response, through TLR/MyD88 signaling in B cells. In this study, by examining Ag-specific B cell response to Qβ-VLP, we found that lack of B cell MyD88 from the beginning of the immune response led to a more severe defect in the GC scale than abolishing MyD88 at later time points of the immune response.

Associations Between Chronic Kidney Disease and Outcomes With Use of Prasugrel Versus Clopidogrel in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A Report From the PROMETHEUS Study.

Objectives: This study sought to compare clinical outcomes in a contemporary acute coronary syndrome (ACS) percutaneous coronary intervention (PCI) cohort stratified by chronic kidney disease (CKD) status.

Background: Patients with CKD exhibit high risks for both thrombotic and bleeding events, thus complicating decision making regarding antiplatelet therapy in the setting of ACS.

Methods: The PROMETHEUS study was a multicenter observational study comparing outcomes with prasugrel versus clopidogrel in ACS PCI patients.

Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells.

Psoriasis is a chronic skin disease associated with deregulated activation of immune cells and keratinocytes. In this study, we used the imiquimod (IMQ)-induced mouse model of psoriasis to dissect better the contribution of hematopoietic and skin-resident stromal cells to psoriasis development. The comparison of disease development in mice carrying the hematopoietic cell-specific deletion of MyD88 ( mice) with mice carrying the total MyD88 deficiency ( mice), we show that the progression of skin and systemic inflammation, as well as of epidermal thickening, was completely dependent on MyD88 expression in hematopoietic cells.

Use of prasugrel vs clopidogrel and outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention in contemporary clinical practice: Results from the PROMETHEUS study.

Background And Objectives: We sought to determine the frequency of use and association between prasugrel and outcomes in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) in clinical practice.

Methods: PROMETHEUS was a multicenter observational registry of acute coronary syndrome patients undergoing PCI from 8 centers in the United States that maintained a prospective PCI registry for patient outcomes. The primary end points were major adverse cardiovascular events at 90days, a composite of all-cause death, nonfatal myocardial infarction, stroke, or unplanned revascularization.

Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9.

Excessive type 2 helper T cell responses to environmental antigens can cause immunopathology such as asthma and allergy, but how such immune responses are induced remains unclear. We studied this process in the airways by immunizing mice intranasally with the antigen ovalbumin together with either of two Toll-like receptor (TLR) ligands. We found the TLR5 ligand flagellin promoted a type 2 helper T cell response, whereas, a TLR9 ligand CpG oligodeoxyribonucleotide (ODN) promoted a type 1 helper T cell response.

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity.

Studies of the genetic factors associated with human autoimmune disease suggest a multigenic origin of susceptibility; however, how these factors interact and through which tolerance pathways they operate generally remain to be defined. One key checkpoint occurs through the activity of the autoimmune regulator AIRE, which promotes central T cell tolerance. Recent reports have described a variety of dominant-negative AIRE mutations that likely contribute to human autoimmunity to a greater extent than previously thought.

Germinal centers and autoimmune disease in humans and mice.

Antibodies are involved in the pathogenesis of many autoimmune diseases. Although the mechanisms underlying the antibody response to infection or vaccination are reasonably well understood, we still have a poor understanding of the nature of autoimmune antibody responses. The most well studied are the anti-nuclear antibody responses characteristic of systemic lupus erythematosus and studies over the past decade or so have demonstrated a critical role for signaling by TLR7 and/or TLR9 in B cells to promote these responses.