Riociguat: Mode of action and clinical development in pulmonary hypertension

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure and increased pulmonary vascular resistance. If untreated, they can result in death due to right heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. Here we describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH, and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and the pivotal Phase III randomized clinical trials in PAH and CTEPH

Long-term benefits of omalizumab in a patient with severe non-allergic asthma

<p>Abstract</p> <p>Introduction</p> <p>Currently, omalizumab is indicated for the treatment of patients with severe allergic uncontrolled asthma despite optimal therapy.</p> <p>Case presentation</p> <p>We studied a 52-year-old man who has been suffering from severe non allergic steroid-resistant asthma with increased levels of total IgE and a lot of comorbidity. After a 3 years long treatment with omalizumab, he presented a significant improvement in disease control in terms of hospitalizations, exacerbation, quality of life and lung function with good safety profile.</p> <p>Conclusion</p> <p>Our case shows, after a long follow-up, how omalizumab can be effective in a severe form of non-atopic asthma. It is therefore hoped that further studies can identify indicators that are able to give to clinicians information about patients who can be responsive to monoclonal anti-IgE antibody even if non allergic.</p

Interactions between rheumatologists and cardio-/pulmonologists in the assessment and use of outcome measures in pulmonary arterial hypertension related to systemic sclerosis

Objectives: Pulmonary arterial hypertension in patients with systemic sclerosis is a disease involving multiple organ systems. We investigated the differences in perceptions of how to measure PAH-SSc among cardiologists, pulmonologists and rheumatologists. We also examined how a Delphi exercise can improve agreement among these subspecialties. Methods: The outcome measures derived from the recent Delphi survey were used for a detailed analysis of the contribution of the various specialties contributing to it. We compared rheumatologists and cardiologist/pulmonologists with regards to preferences and ratings of various endpoints and the actual use of tools to measure these outcomes. We also examined the effects of the Delphi process among these groups. Results: We could show that the different expert groups each tended to contribute differently to the development of the core set of measures and that interactions in the Delphi process resulted in convergence of rankings. Despite agreement on the high importance of the domains in the Delphi, the use of tools within those domains was sometimes divergent and dependent on specialty. Conclusions: Based on these results, use of differing tools in the diagnosis and treatment of PAH-SSc can be anticipated. Further, the convergence of results provides evidence, for the first time, for the ability of various approaches in these disciplines to reach harmonious endpoints of care for PAHSSc patients. A collaborative, interdisciplinary approach is advantageous for PAH-SSc patients

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension

<p>Abstract</p> <p>Background</p> <p>Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (<it>BMPR2</it>) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between <it>BMPR2 </it>mutation carriers and noncarriers, it is likely disease severity is not equal among <it>BMPR2 </it>mutations. We hypothesized that patients with missense <it>BMPR2 </it>mutations have more severe disease than those with truncating mutations.</p> <p>Methods</p> <p>Testing for <it>BMPR2 </it>mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable <it>BMPR2 </it>mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between <it>BMPR2 </it>mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation.</p> <p>Results</p> <p>While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the <it>BMPR2 </it>mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years.</p> <p>Conclusion</p> <p>In this cohort, <it>BMPR2 </it>mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at <it>BMPR2 </it>pathway defects may need to vary according to the type of mutation.</p

Author correction : a global database for metacommunity ecology, integrating species, traits, environment and space

Correction to: Scientific Data https://doi.org/10.1038/s41597-019-0344-7, published online 08 January 202

Author correction : a global database for metacommunity ecology, integrating species, traits, environment and space

Correction to: Scientific Data https://doi.org/10.1038/s41597-019-0344-7, published online 08 January 202

Inducing Cross-Clade Neutralizing Antibodies against HIV-1 by Immunofocusing

Background: Although vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens. Methodology/Principal Findings: Using random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simianhuman immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages. Conclusions/Significance: This strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies and cross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antige

Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients