Utility of factor D and other alternative complement factors as biomarkers in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH).

Background: Activation of the complement cascade is thought to play a role in scleroderma vasculopathy. We previously showed that complement factor D was elevated in patients with limited cutaneous SSc and pulmonary arterial hypertension (PAH). In this study, we sought to assess multiple relevant components of the complement cascade to determine if they are altered in SSc-PAH, as well as their potential utility as biomarkers of disease severity and progression.

Thy-1 plays a pathogenic role and is a potential biomarker for skin fibrosis in scleroderma.

Thy-1 (CD90) is a well-known marker of fibroblasts implicated in organ fibrosis, but its contribution to skin fibrosis remains unknown. We examined Thy-1 expression in scleroderma skin and its potential role as a biomarker and pathogenic factor in animal models of skin fibrosis. Skin from patients with systemic sclerosis demonstrated markedly elevated Thy-1 expression compared with controls, colocalized with fibroblast activator protein in the deep dermis, and correlated with the severity of skin involvement (modified Rodnan skin score).

PLG nanoparticles target fibroblasts and MARCO+ monocytes to reverse multiorgan fibrosis.

Systemic sclerosis (SSc) is a chronic, multisystem orphan disease with a highly variable clinical course, high mortality rate, and a poorly understood complex pathogenesis. We have identified an important role for a subpopulation of monocytes and macrophages characterized by surface expression of the scavenger receptor macrophage receptor with collagenous structure (MARCO) in chronic inflammation and fibrosis in SSc and in preclinical disease models. We show that MARCO+ monocytes and macrophages accumulate in lesional skin and lung in topographic proximity to activated myofibroblasts in patients with SSc and in the bleomycin-induced mouse model of SSc.

Circulating CTRP9 Is Associated With Severity of Systemic Sclerosis-Associated Interstitial Lung Disease.

Objective: While interstitial lung disease (ILD) is the leading cause of morbidity and mortality in systemic sclerosis (SSc), there remains a paucity of predictive markers to assess disease progression. We previously demonstrated that adipose tissue metabolism and adipokine homeostasis is dysregulated in SSc. The present study was undertaken to determine the association and predictive ability of the novel adipokine C1q/tumor necrosis factor-related protein 9 (CTRP9) for SSc-associated ILD.

Pathological pulmonary vascular remodeling is induced by type V collagen in a model of scleroderma.

Objective: The pulmonary vascular remodeling in systemic sclerosis (SSc) is poorly understood and animal models are lacking. Type V collagen (COLV) is elevated in SSc and is implicated in the pathogenesis, and immunization with human COLV induces SSc-like skin and lung changes in rabbits and mice. Here we tested the hypothesis that COLV immunization will induce pathological and functional changes that phenocopy SSc-associated pulmonary vascular disease.

Targeting CD38-dependent NAD metabolism to mitigate multiple organ fibrosis.

The processes underlying synchronous multiple organ fibrosis in systemic sclerosis (SSc) remain poorly understood. Age-related pathologies are associated with organismal decline in nicotinamide adenine dinucleotide (NAD) that is due to dysregulation of NAD homeostasis and involves the NADase CD38. We now show that CD38 is upregulated in patients with diffuse cutaneous SSc, and CD38 levels in the skin associate with molecular fibrosis signatures, as well as clinical fibrosis scores, while expression of key NAD-synthesizing enzymes is unaltered.

Adipocytic Progenitor Cells Give Rise to Pathogenic Myofibroblasts: Adipocyte-to-Mesenchymal Transition and Its Emerging Role in Fibrosis in Multiple Organs.

Purpose Of Review: Adipocytes have recently been shown to be able to reprogram to a myofibroblastic phenotype in a process termed adipocyte mesenchymal transition (AMT). This review seeks to discuss the relevance of this process to disease and explore its mechanisms.

Recent Findings: AMT occurs in multiple organs and diseases, transdifferentiation goes through a precursor cell and there is a reversible process that can be influenced by metabolic stress, myeloid cells, immune dysregulation, and pharmacological intervention.

High-throughput quantitative histology in systemic sclerosis skin disease using computer vision.

Background: Skin fibrosis is the clinical hallmark of systemic sclerosis (SSc), where collagen deposition and remodeling of the dermis occur over time. The most widely used outcome measure in SSc clinical trials is the modified Rodnan skin score (mRSS), which is a semi-quantitative assessment of skin stiffness at seventeen body sites. However, the mRSS is confounded by obesity, edema, and high inter-rater variability.

The JAK/STAT pathway is activated in systemic sclerosis and is effectively targeted by tofacitinib.

Rationale: Fibrosis leads to failure of the skin, lungs, and other organs in systemic sclerosis; accounts for substantial morbidity and mortality; and lacks effective therapy. Myofibroblast activation underlies organ fibrosis, but the key extracellular cues driving persistence of the process remain incompletely characterized.

Objectives: The objectives were to evaluate activation of the IL6/JAK/STAT axis associated with fibrosis in skin and lung biopsies from systemic sclerosis patients and effects of the Food and Drug Administration-approved JAK/STAT inhibitor, tofacitinib, on skin and lung fibrosis in animal models.

Soft tissue necrosis in patients treated with transoral robotic surgery and postoperative radiotherapy: preliminary results.

Objective: Postoperative radiotherapy (PORT) is indicated in almost two-thirds of patients treated with transoral robotic surgery (TORS) for head and neck tumors. The aim of this study was to quantify the toxicity profile of patients treated with PORT after TORS in oropharyngeal and supraglottic laryngeal cancer focusing on soft tissue necrosis (STN).

Methods: We retrospectively reviewed 28 patients.

Clinical features and management of antrochoanal polyps in children: Cues from a clinical series of 58 patients.

Objective: To review the clinical features of pediatric patients affected by antrochoanal polyps (ACPs) and surgically treated at three University settings.

Methods: Retrospective study. The present research includes the clinical data of subjects affected by ACPs, aged <18 years and referred to three ENT Departments, between January 1st 2003 and September 30th 2016.

Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis.

Background: A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-γ is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-γ (PPAR-γ) has antifibrotic effects by blocking transforming growth factor-β (TGF-β) and is dysregulated in SSc.

The non-neuronal cyclin-dependent kinase 5 is a fibrotic mediator potentially implicated in systemic sclerosis and a novel therapeutic target.

The mechanisms underlying persistent fibroblast activation and myofibroblast phenoconversion in underlying multi-organ fibrosis in systemic sclerosis (SSc) remain incompletely understood, hindering effective therapies to slow or reverse the process. Cyclin-dependent kinase 5 (CDK5) is a pleiotropic member of the CDK family originally identified in neuronal cells. In contrast to other CDKs, CDK5 activity depends on its CDK5R1 subunit p35.

Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease.

Background: There are no effective treatments or validated clinical response markers in systemic sclerosis (SSc). We assessed imaging biomarkers and performed gene expression profiling in a single-arm open-label clinical trial of tyrosine kinase inhibitor dasatinib in patients with SSc-associated interstitial lung disease (SSc-ILD).

Methods: Primary objectives were safety and pharmacokinetics.

The roles of dermal white adipose tissue loss in scleroderma skin fibrosis.

Purpose Of Review: Dermal white adipose tissue (DWAT) is distinct from subcutaneous white adipose tissue and is lost in scleroderma skin fibrosis. The roles of DWAT loss in scleroderma skin fibrosis have not been well understood, and here we discuss recent findings that begin to provide insight into the multiple mechanisms involved.

Recent Findings: The DWAT loss in part reflects the direct contribution of DWAT cells to the fibrotic tissue, with the reprogramming of adipocytes to myofibroblasts.

Adiponectin is an endogenous anti-fibrotic mediator and therapeutic target.

Skin fibrosis in systemic sclerosis (SSc) is accompanied by attrition of dermal white adipose tissue (dWAT) and reduced levels of circulating adiponectin. Since adiponectin has potent regulatory effects on fibroblasts, we sought to assess adiponectin signaling in SSc skin biopsies, and evaluate fibrosis in mice with adiponectin gain- and loss-of-function mutations. Furthermore, we investigated the effects and mechanism of action of agonist peptides targeting adiponectin receptors in vitro and in vivo.

Brief Report: Association of Elevated Adipsin Levels With Pulmonary Arterial Hypertension in Systemic Sclerosis.

Objective: Adipose tissues secrete adipokines, peptides with potent effects modulating fibrosis, inflammation, and vascular homeostasis. Dysregulated adipose tissue biology and adipokine balance have recently been implicated in systemic sclerosis (SSc). This study was undertaken to determine whether altered circulating adipokine levels correlate with SSc disease subsets or clinical manifestations.

Hypopharyngeal squamous cell carcinoma and laryngeal neuroendocrine carcinoma colliding in the aryepiglottic fold: a case report.

Purpose: A collision tumor consists of 2 different histologically distinct and topographically independent tumors merging in the same mass. In the head and neck region they are rare, with only 4 cases reported in the larynx.

Case Report: A 60-year-old heavy smoker complained of a left submandibular lesion in October 2014.

Nrf2 exerts cell-autonomous antifibrotic effects: compromised function in systemic sclerosis and therapeutic rescue with a novel heterocyclic chalcone derivative.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) governs antioxidant, innate immune and cytoprotective responses and its deregulation is prominent in chronic inflammatory conditions. To examine the hypothesis that Nrf2 might be implicated in systemic sclerosis (SSc), we investigated its expression, activity, and mechanism of action in SSc patient samples and mouse models of fibrosis and evaluated the effects of a novel pharmacologic Nrf2 agonist. We found that both expression and activity of Nrf2 were significantly reduced in SSc patient skin biopsies and showed negative correlation with inflammatory gene expression.

Animal models of scleroderma: recent progress.

Purpose Of Review: We discuss recent advances in evaluating and optimizing animal models of systemic sclerosis (SSc). Such models could be of value for illuminating etiopathogenesis using hypothesis-testing experimental approaches, for developing effective disease-modifying therapies, and for uncovering clinically relevant biomarkers.

Recent Findings: We describe recent advances in previously reported and novel animal models of SSc.