Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study

Background

Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH.

Methods

We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n =?84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints.

Results

In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean?±?standard deviation 6MWD had increased by 33?±?42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups.

Conclusions

Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed.

Trial registration

ClinicalTrials.org NCT01784562. Registered February 4, 2013.

     

Competition for dead trees between humans and aye-ayes (<Emphasis Type="Italic">Daubentonia madagascariensis</Emphasis>) in central eastern Madagascar

The destruction and degradation of forest habitats are major threats to the sustainability of lemur populations in Madagascar. Madagascan landscapes often contain forest fragments that represent refuges for native fauna, while also being used for firewood and timber by local human populations. As undisturbed forest becomes increasingly scarce, understanding resource competition between humans and wildlife in disturbed habitats will be increasingly important. We tested the hypothesis that Malagasy and aye-ayes (Daubentonia madagascariensis) compete for the limited number of dead trees in rainforest fragments at Tsinjoarivo, Madagascar. We surveyed 2.16 ha within five fragments (range 5–228 ha) surrounding human settlements to quantify the density of dead trees and traces of both human and aye-aye activity. Neither aye-aye nor human traces were distributed according to the availability of particular trees species, and aye-ayes and Malagasy apparently preferred several different species. Although overlap was recorded in tree species used, human use tended to be positively correlated with a species’ desirability as firewood, while a negative relationship was seen for aye-ayes. Both consumers used trees of similar diameter at breast height, but those used by aye-ayes tended to be older, suggesting that human use might precede usefulness for aye-ayes. Finally, the density of dead trees and aye-aye traces were highest in smaller fragments, but human traces did not vary across fragment size. Although further study is needed to better quantify the aye-aye diet in this region, these data suggest that aye-ayes and local people compete for dead trees, and this competition could constitute a pressure on aye-aye populations.     

Kinetics of intracolloidal iodine within the thyroid of newborn rats. Direct imagery using secondary ion mass spectrometry

The spatiotemporal distribution of cellular uptake site of radiotoxics is essential data for microdosimetric studies. As early as 1950, the heterogeneity of iodine incorporation within the thyroid has been shown using autoradiography. The objective of this study is to describe the kinetic cellular distribution of newly organified iodine in the thyroid of newborn rats using secondary ion mass microscopy (NanoSIMS50). Ionic images obtained at high mass resolution and with a lateral resolution of about 50 nm show that the early distribution of iodine is heterogeneous from one follicle to another, from one thyrocyte to another inside the same follicle, and that this distribution varies as a function of time. The obtained kinetic profile will allow us to refine the studies concerning the aetiopathology of thyroid cancers of the Chernobyl children.     

Are Eating Occasions and Their Energy Content Related to Child Overweight and Socioeconomic Status?

The objectives of this study were: (i) to assess the relationships between childhood overweight (OW) and four eating behaviors: daily eating frequency, and the relative contribution of breakfast, main meals (lunch and dinner), and snacks to total daily energy intake (EI); (ii) to explore whether these eating behaviors are involved in the negative association between socioeconomic status (SES) and OW. A representative sample of French children aged 3-11 years (n = 748) was taken from the 1998-1999 cross-sectional French INCA1 (Enquête Individuelle et Nationale sur les Consommations Alimentaires) food consumption survey. Food intake was reported in a 7-day food record, and SES, physical activity, sedentary behavior (SED), weight, and height were reported by answering face-to-face questionnaires. After adjusting for EI, physical activity, and SED, OW was positively associated with the contribution of the main meals to EI (P = 0.03), not significantly associated with the contribution of breakfast to EI, and inversely correlated to the number of eating episodes (P = 0.009) and to the contribution of snacking episodes to EI (P = 0.007). Our data suggest that a combination of more frequent intake occasions and lower contribution of the main meals to total daily EI is associated with a smaller risk of OW in children. However, eating frequency was the only eating behavior that played a slight mediation role (contributing approximately 8%) in the inverse relationship between SES and OW.     

Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD

Background

The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.

Methodology/Principal Findings

Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.

Conclusion/Significance

Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.     

Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is known to protect tumor cells from apoptosis and more specifically from the Fas-mediated apoptotic signal. The antitumoral agent edelfosine sensitizes leukemic cells to death by inducing the redistribution of the apoptotic receptor Fas into plasma membrane subdomains called lipid rafts. Herein, we show that inhibition of the PI3K signal by edelfosine triggers a Fas-mediated apoptotic signal independently of the Fas/FasL interaction. Furthermore, similarly to edelfosine, blockade of the PI3K activity, using specific inhibitors LY294002 and wortmannin, leads to the clustering of Fas whose supramolecular complex is colocalized within the lipid rafts. These findings indicate that the antitumoral agent edelfosine down-modulates the PI3K signal to sensitize tumor cells to death through the redistribution of Fas into large platform of membrane rafts.     

Japanese medaka Hox paralog group 2: insights into the evolution of Hox PG2 gene composition and expression in the Osteichthyes

Hox paralog group 2 (PG2) genes function to specify the development of the hindbrain and pharyngeal arch-derived structures in the Osteichthyes. In this article, we describe the cDNA cloning and embryonic expression analysis of Japanese medaka (Oryzias latipes) Hox PG2 genes. We show that there are only two functional canonical Hox genes, hoxa2a and b2a, and that a previously identified hoxa2b gene is a transcribed pseudogene, psihoxa2b. The functional genes, hoxa2a and b2a, were expressed in developing rhombomeres and pharyngeal arches in a manner that was relatively well conserved compared with zebrafish (Danio rerio) but differed significantly from orthologous striped bass (Morone saxatilis) and Nile tilapia (Oreochromis niloticus) genes, which, we suggest, may be owing to effects of post-genome duplication loss of a Hox PG2 gene in the medaka and zebrafish lineages. psihoxa2b was expressed at readily detectable levels in several noncanonical Hox expression domains, including the ventral aspect of the neural tube, the pectoral fin buds and caudal-most region of the embryonic trunk, indicative that regulatory control elements needed for spatio-temporal expression have diverged from their ancestral counterparts. Comparative expression analyses showed medaka hoxa2a and b2a expression in the 2nd pharyngeal arch (PA2) beyond the onset of chondrogenesis, which, according to previous hypotheses, suggests these genes function redundantly as selector genes of PA2 identity. We conclude that Hox PG2 gene composition and expression have diverged significantly during osteichthyan evolution and that this divergence in teleosts may be related to lineage-dependent differential gene loss following an actinopterygian-specific whole genome duplication.     

Model-based clustering on the unit sphere with an illustration using gene expression profiles

We consider model-based clustering of data that lie on a unit sphere. Such data arise in the analysis of microarray experiments when the gene expressions are standardized so that they have mean 0 and variance 1 across the arrays. We propose to model the clusters on the sphere with inverse stereographic projections of multivariate normal distributions. The corresponding model-based clustering algorithm is described. This algorithm is applied first to simulated data sets to assess the performance of several criteria for determining the number of clusters and to compare its performance with existing methods and second to a real reference data set of standardized gene expression profiles.     

Architecture of the large membrane-bound mucins

Epithelial membrane-bound mucins are high molecular mass glycoproteins that may be also secreted or released into the extracellular environment. The genomic and multi-domain organizations of human large epithelial membrane-bound mucins are reviewed here with the purpose to clarify the literature on the subject with the help of mouse sequences. This family of complex molecules contains at least MUC3A, MUC12, MUC17, all organized in a cluster of genes, MUC4 and likely MUC16. In addition, we discuss the splicing events reported for these mucins with an emphasis on the human mucin MUC4.