Application of REVEAL Lite 2 and COMPERA 2.0 risk scores to patients with pulmonary arterial hypertension switching to riociguat in the REPLACE study.

In Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) (NCT02891850), improvements in risk status were observed in patients with pulmonary arterial hypertension (PAH) at intermediate risk switching to riociguat versus continuing phosphodiesterase-5 inhibitors (PDE5i). This post hoc study applied the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 and Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary (COMPERA) 2.0 risk-assessment tools to REPLACE to investigate the impact of baseline risk status on clinical improvement.

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.

Background: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality.

Correction to: Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH.

The original version of this article unfortunately contained a mistake. In the "Results" section, the percentage of patients with inoperable or persistent/recurrent CTEPH included in the study was reported as 85%. This has been corrected to 68% with this erratum.

Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH.

Purpose: A proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice.

RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors.

A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study.

Bipartite recognition of DNA by TCF/Pangolin is remarkably flexible and contributes to transcriptional responsiveness and tissue specificity of wingless signaling.

The T-cell factor (TCF) family of transcription factors are major mediators of Wnt/β-catenin signaling in metazoans. All TCFs contain a High Mobility Group (HMG) domain that possesses specific DNA binding activity. In addition, many TCFs contain a second DNA binding domain, the C-clamp, which binds to DNA motifs referred to as Helper sites.

Distinct DNA binding sites contribute to the TCF transcriptional switch in C. elegans and Drosophila.

Regulation of gene expression by signaling pathways often occurs through a transcriptional switch, where the transcription factor responsible for signal-dependent gene activation represses the same targets in the absence of signaling. T-cell factors (TCFs) are transcription factors in the Wnt/ß-catenin pathway, which control numerous cell fate specification events in metazoans. The TCF transcriptional switch is mediated by many co-regulators that contribute to repression or activation of Wnt target genes.

The pro-atherogenic effects of macrophages are reduced upon formation of a complex between C-reactive protein and lysophosphatidylcholine.

Rationale: C-reactive protein (CRP) and lysophosphatidylcholine (LPC) are phosphorylcholine-(PC)-containing oxidized phospholipids (oxPLs) found in oxidized LDL (oxLDL), which trigger pro-atherogenic activities of macrophages during the process of atherosclerosis. It has been previously reported that CRP binds to the PC head group of oxLDL in a calcium-dependent manner. The aim of this study was to investigate the importance of binding between CRP and LPC to the pro-atherogenic activities of macrophages.

Activation of wingless targets requires bipartite recognition of DNA by TCF.

Specific recognition of DNA by transcription factors is essential for precise gene regulation. In Wingless (Wg) signaling in Drosophila, target gene regulation is controlled by T cell factor (TCF), which binds to specific DNA sequences through a high mobility group (HMG) domain. However, there is considerable variability in TCF binding sites, raising the possibility that they are not sufficient for target location.

The chromatin remodelers ISWI and ACF1 directly repress Wingless transcriptional targets.

The highly conserved Wingless/Wnt signaling pathway controls many developmental processes by regulating the expression of target genes, most often through members of the TCF family of DNA-binding proteins. In the absence of signaling, many of these targets are silenced, by mechanisms involving TCFs that are not fully understood. Here we report that the chromatin remodeling proteins ISWI and ACF1 are required for basal repression of WG target genes in Drosophila.

Regulation of the feedback antagonist naked cuticle by Wingless signaling.

Signaling pathways usually activate transcriptional targets in a cell type-specific manner. Notable exceptions are pathway-specific feedback antagonists, which serve to restrict the range or duration of the signal. These factors are often activated by their respective pathways in a broad array of cell types.

Novel TCF-binding sites specify transcriptional repression by Wnt signalling.

Both transcriptional activation and repression have essential functions in maintaining proper spatial and temporal control of gene expression. Although Wnt signalling is often associated with gene activation, we have identified several directly repressed targets of Wnt signalling in Drosophila. Here, we explore how individual Wnt target genes are specified for signal-induced activation or repression.

The role of natural antibodies in atherogenesis.

Atherosclerosis is now widely recognized as a chronic inflammatory disease that involves innate and adaptive immune responses. Both cellular and humoral components of the immune system have been implicated in atherogenesis. Natural antibodies can be considered humoral factors of innate immunity, and their functional role in health and disease has been reexamined in recent years.

Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.

Oxidation of low density lipoprotein (LDL) generates a variety of oxidatively modified lipids and lipid-protein adducts that are immunogenic and proinflammatory, which in turn contribute to atherogenesis. Cells undergoing apoptosis also display oxidized moieties on their surface membranes, as determined by binding of oxidation-specific monoclonal antibodies. In the present paper, we demonstrated by mass spectrometry that in comparison with viable cells, membranes of cells undergoing apoptosis contain increased levels of biologically active oxidized phospholipids (OxPLs).

IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis.

During atherogenesis, LDL is oxidized, generating various oxidation-specific neoepitopes, such as malondialdehyde-modified (MDA-modified) LDL (MDA-LDL) or the phosphorylcholine (PC) headgroup of oxidized phospholipids (OxPLs). These epitopes are recognized by both adaptive T cell-dependent (TD) and innate T cell-independent type 2 (TI-2) immune responses. We previously showed that immunization of mice with MDA-LDL induces a TD response and atheroprotection.

Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK.

To clarify the role of caveolae in VEGF/VEGF receptor-2 (VEGFR-2)-mediated signaling cascades, primary cultured human umbilical vein endothelial cells (HUVECs) were fractionated to isolate caveolae-enriched cell membranes. Interestingly, VEGFR-2, phospholipase D2 (PLD2), and Ras were enriched in caveolae-enriched fractions. Moreover, VEGF increased PLD activity in a time- and dose-dependent manner in HUVECs, whereas a ligand specific for VEGFR-1 placental growth factor did not change PLD activity.

Oxidized low density lipoprotein and innate immune receptors.

Purpose Of Review: Atherosclerosis is now recognized as a chronic inflammatory disease. This review discusses recent literature reporting that innate immune receptors bind oxidatively modified LDL and its many oxidized moieties and consequently modulate the atherogenic process. These innate pattern recognition receptors are known to play a central role in pro-inflammatory responses to bacteria by binding pathogen-associated molecular patterns.

The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells.

Abs specific for phosphorylcholine (PC) are known to contribute to the immune defense against a variety of microbial infections. To assess for other types of binding interactions, we performed surveys of anti-PC Abs of diverse biologic origins and structural diversity and demonstrated a common autoreactivity for oxidatively modified low density lipoprotein and other oxidation-specific structures containing PC-Ags. We also found that cells undergoing apoptosis sequentially express a range of oxidation-specific neo-self PC determinants.

Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.

During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae.

C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids.

C-reactive protein (CRP) is an acute-phase protein that binds specifically to phosphorylcholine (PC) as a component of microbial capsular polysaccharide and participates in the innate immune response against microorganisms. CRP elevation also is a major risk factor for cardiovascular disease. We previously demonstrated that EO6, an antioxidized LDL autoantibody, was a T15 clono-specific anti-PC antibody and specifically binds to PC on oxidized phosphatidylcholine (PtC) but not on native PtC.