Long-term safety and efficacy of trifarotene 50 μg/g cream, a first-in-class RAR-γ selective topical retinoid, in patients with moderate facial and truncal acne.

BackgroundTreatment for both facial and truncal acne has not sufficiently been studied.ObjectivesTo evaluate the long-term safety and efficacy of trifarotene in both facial and truncal acne.MethodsIn a multicentre, open-label, 52-week study, patients with moderate facial and truncal acne received trifarotene 50 μg/g cream (trifarotene). Assessments included local tolerability, safety, investigator and physician's global assessments (IGA, PGA) and quality of life (QOL). A validated QOL questionnaire was completed by the patient at Baseline, Week 12, 26 and 52/ET.ResultsOf 453 patients enrolled, 342 (75.5%) completed the study. Trifarotene-related treatment-emergent adverse events (TEAEs) were reported in 12.6% of patients, and none was serious. Most related TEAEs were cutaneous and occurred during the first 3 months. Signs and symptoms of local tolerability were mostly mild or moderate and severe signs, and symptoms were reported for 2.2% to 7.1% of patients for the face and 2.5% to 5.4% for the trunk. Local irritation increased during the first week of treatment on the face and up to Weeks 2 to 4 on the trunk with both decreasing thereafter. At Week 12, IGA and PGA success rates were 26.6% and 38.6%, respectively. Success rates increased to 65.1% and 66.9%, respectively at Week 52. Overall success (both IGA and PGA success in the same patient) was 57.9% at Week 52. At Week 52 visit, 92/171 (53.8%) patients who had completed their assessments had scores from 0 to 1 (i.e. no effect of acne on their QOL) vs. 47/208 (22.6%) patients at Baseline visit.ConclusionIn this 52-week study, trifarotene was safe, well tolerated and effective in moderate facial and truncal acne

Extending critical performativity

In this article we extend the debate about critical performativity. We begin by outlining the basic tenets of critical performativity and how this has been applied in the study of management and organization. We then address recent critiques of critical performance. We note these arguments suffer from an undue focus on intra-academic debates; engage in author-itarian theoretical policing; feign relevance through symbolic radicalism; and repackage common sense. We take these critiques as an opportunity to offer an extended model of critical performativity that involves focusing on issues of public importance; engaging with non-academic groups using dialectical reasoning; scaling up insights through movement building; and propagating deliberation

Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule.

Progressive organ fibrosis accounts for one-third of all deaths worldwide, yet preclinical models that mimic the complex, progressive nature of the disease are lacking, and hence, there are no curative therapies. Progressive fibrosis across organs shares common cellular and molecular pathways involving chronic injury, inflammation, and aberrant repair resulting in deposition of extracellular matrix, organ remodeling, and ultimately organ failure. We describe the generation and characterization of an in vitro progressive fibrosis model that uses cell types derived from induced pluripotent stem cells. Our model produces endogenous activated transforming growth factor β (TGF-β) and contains activated fibroblastic aggregates that progressively increase in size and stiffness with activation of known fibrotic molecular and cellular changes. We used this model as a phenotypic drug discovery platform for modulators of fibrosis. We validated this platform by identifying a compound that promotes resolution of fibrosis in in vivo and ex vivo models of ocular and lung fibrosis

Functional Restoration of CFTR Nonsense Mutations in Intestinal Organoids

Background: Pharmacotherapies for people with cystic fibrosis (pwCF) who have premature termination codons (PTCs) in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are under development. Thus far, clinical studies focused on compounds that induce translational readthrough (RT) at the mRNA PTC location. Recent studies using primary airway cells showed that PTC functional restoration can be achieved through combining compounds with multiple mode-of-actions. Here, we assessed induction of CFTR function in PTC-containing intestinal organoids using compounds targeting RT, nonsense mRNA mediated decay (NMD) and CFTR protein modulation. Methods: Rescue of PTC CFTR protein was assessed by forskolin-induced swelling of 12 intestinal organoid cultures carrying distinct PTC mutations. Effects of compounds on mRNA CFTR level was assessed by RT-qPCRs. Results: Whilst response varied between donors, significant rescue of CFTR function was achieved for most donors with the quintuple combination of a commercially available pharmacological equivalent of the RT compound (ELX-02-disulfate or ELX-02ds), NMD inhibitor SMG1i, correctors VX-445 and VX-661 and potentiator VX-770. The quintuple combination of pharmacotherapies reached swelling quantities higher than the mean swelling of three VX-809/VX-770-rescued F508del/F508del organoid cultures, indicating level of rescue is of clinical relevance as VX-770/VX-809-mediated F508del/F508del rescue in organoids correlate with substantial improvement of clinical outcome. Conclusions: Whilst variation in efficacy was observed between genotypes as well as within genotypes, the data suggests that strong pharmacological rescue of PTC requires a combination of drugs that target RT, NMD and protein function

Creating the collective: social media, the Occupy Movement and its constitution as a collective actor

This paper examines the process through which Occupy activists came to constitute themselves as a collective actor and the role of social media in this process. The theoretical framework combines Melucci's (1996) theory of collective identity with insights from the field of organizational communication and particularly from the ‘CCO’ strand – short for ‘Communication is Constitutive of Organizing’. This allows us to conceptualize collective identity as an open-ended and dynamic process that is constructed in conversations and codified in texts. Based on interviews with Occupy activists in New York, London and other cities, I then discuss the communication processes through which the movement was drawing the boundaries with its environment, creating codes and foundational documents, as well as speaking in a collective voice. The findings show that social media tended to blur the boundaries between the inside and the outside of the movement in a way that suited its values of inclusiveness and direct participation. Social media users could also follow remotely the meetings of the general assembly where the foundational documents were ratified, but their voices were not included in the process. The presence of the movement on social media also led to conflicts and negotiations around Occupy's collective voice as constructed on these platforms. Thus, viewing the movement as a phenomenon emerging in communication allows us an insight into the efforts of Occupy activists to create a collective that was both inclusive of the 99% and a distinctive actor with its own identity

Troubling stories of the end of occupy : feminist narratives of betrayal at occupy Glasgow

This article offers a feminist take on the question of why Occupy camps closed down, in the form of a narrative analysis of interviews from participants in Occupy Glasgow. In response to the emergence of an activist discourse emphasising the role of external forces in camp closure and the existence of a longer-term legacy in terms of individual and community politicisation, I build here on feminist interventions that point instead to serious internal problems within the camps and thus to a more limited legacy. Interrogating the plotting, characterisation and denouement of interviewee narratives, I show that feminist participants in Occupy Glasgow characterise the trajectory of the camp as a tragedy, attribute responsibility for the camp’s demise to co-campers and sometimes to themselves, and present the outcome of Occupy Glasgow as limited, and in some cases even traumatic. This raises serious questions about the culmination and outcomes of Occupy in Glasgow and more generally, and indicates the extent of the hard work remaining if future mobilisation against neoliberal austerity is to be more inclusive and sustainable. The article closes by considering the theoretical implications for the wider question of why movements come to an end

Maximal entropy inference of oncogenicity from phosphorylation signaling

Point mutations in the phosphorylation domain of the Bcr-Abl fusion oncogene give rise to drug resistance in chronic myelogenous leukemia patients. These mutations alter kinase-mediated signaling function and phenotypic outcome. An information theoretic analysis of the correlation of phosphoproteomic profiling and transformation potency of the oncogene in different mutants is presented. The theory seeks to predict the leukemic transformation potency from the observed signaling by constructing a distribution of maximal entropy of site-specific phosphorylation events. The theory is developed with special reference to systems biology where high throughput measurements are typical. We seek sets of phosphorylation events most contributory to predicting the phenotype by determining the constraints on the signaling system. The relevance of a constraint is measured by how much it reduces the value of the entropy from its global maximum, where all events are equally likely. Application to experimental phospho-proteomics data for kinase inhibitor-resistant mutants shows that there is one dominant constraint and that other constraints are not relevant to a similar extent. This single constraint accounts for much of the correlation of phosphorylation events with the oncogenic potency and thereby usefully predicts the trends in the phenotypic output. An additional constraint possibly accounts for biological fine structure