UCHL1-dependent control of hypoxia-inducible factor transcriptional activity during liver fibrosis.

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver disease. At the cellular level, liver fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast-like phenotype that is contractile, proliferative and profibrogenic. HSC transdifferentiation induces genome-wide changes in gene expression that enable the cell to adopt its profibrogenic functions. We have previously identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation; however, the cellular targets of its deubiquitinating activity are poorly defined. Here, we describe a role for UCHL1 in regulating the levels and activity of hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, during HSC activation and liver fibrosis. HIF1 is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. Increased HIF1α expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1α levels. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. As we also show that UCHL1 inhibition blunts fibrogenesis in a pre-clinical 3D human liver slice model of fibrosis, these results demonstrate how small molecule inhibitors of DUBs can exert therapeutic effects through modulation of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity using UCHL1 inhibitors may represent a therapeutic opportunity with other HIF-related pathologies.

miRNA Expression in Fibroblastic Foci within Idiopathic Pulmonary Fibrosis Lungs Reveals Novel Disease-Relevant Pathways.

miRNAs are 22 nucleotides long and belong to a class of noncoding RNAs that plays an important role in regulating gene expression at a post-transcriptional level. Studies show aberrant levels of miRNAs to be associated with profibrotic processes in idiopathic pulmonary fibrosis (IPF). However, most of these studies used whole IPF tissue or in vitro monocultures in which fibrosis was artificially induced. The current study used laser microdissection to collect fibroblastic foci (FF), the key pathologic lesion in IPF, isolated miRNAs, and compared their expression levels with those found in whole IPF lung tissue and/or in vitro cultured fibroblast from IPF or normal lungs. Sequencing libraries were generated, and data generated were bioinformatically analyzed. A total of 18 miRNAs were significantly overexpressed in FF tissue when compared with whole IPF tissue. Of those, 15 were unique to FF. Comparison of FF with cultured IPF fibroblasts also revealed differences in miRNA composition that impacted several signaling pathways. The miRNA composition of FF is both overlapping and distinct from that of whole IPF tissue or cultured IPF fibroblasts and highlights the importance of characterizing FF biology as a phenotypically and functionally discrete tissue microenvironment.

Angioleiomyoma of the Larynx: A Case Report and Literature Review.

Angioleiomyoma is a benign smooth muscle and vessel tumor; laryngeal localization is extremely rare with only 24 cases described in the literature; moreover, it should be considered in the differential diagnosis of laryngeal mass. Endoscopic complete surgical excision with dissection along capsule is now considered the gold-standard treatment for small and well-circumscribed laryngeal angioleiomyoma. We present a case of laryngeal angioleiomyoma successfully treated with carbon dioxide laser technology which resulted in a bleeding reduction and adequate hemostasis with less tissue damage and good functional outcome.

A modular informatics platform for effective support of collaborative and multicenter studies in cardiology.

Collaborative and multicenter studies permit a large number of patients to be enrolled within a reasonable time and providing the opportunity to collect different data. Informatics platforms play an important role in management, storage, and exchange of data between the participants involved in the study. In this article, we describe a modular informatics platform designed and developed to support collaborative and multicenter studies in cardiology. In each developed module, data management is implemented following local defined protocols. The modular characteristic of the developed platform allows independent transfer of different kinds of data, such as biological samples, imaging raw data, and patients' digital information. Moreover, it offers safe central storage of the data collected during the study. The developed platform was successfully tested during a European collaborative and multicenter study, focused on evaluating multimodal non-invasive imaging to diagnose and characterize ischemic heart disease.

Hybrid image visualization tool for 3D integration of CT coronary anatomy and quantitative myocardial perfusion PET.

PURPOSE: Multimodal cardiac imaging by CTA and quantitative PET enables acquisition of patient-specific coronary anatomy and absolute myocardial perfusion at rest and during stress. In the clinical setting, integration of this information is performed visually or using coronary arteries distribution models. We developed a new tool for CTA and quantitative PET integrated 3D visualization, exploiting XML and DICOM clinical standards. METHODS: The hybrid image tool (HIT) developed in the present study included four main modules: (1) volumetric registration for spatial matching of CTA and PET data sets, (2) an interface to PET quantitative analysis software, (3) a derived DICOM generator able to build DICOM data set from quantitative polar maps, and (4) a 3D visualization tool of integrated anatomical and quantitative flow information. The four modules incorporated in the HIT tool communicate by defined standard XML files: XML-transformation and XML MIST standards. RESULTS: The HIT tool implements a 3D representation of CTA showing real coronary anatomy fused to PET-derived quantitative myocardial blood flow distribution. The technique was validated on 16 data sets from EVINCI study population. The validation of the method confirmed the high matching between "original" and derived data sets as well as the accuracy of the registration procedure. CONCLUSIONS: Three-dimensional integration of patient- specific coronary artery anatomy provided by CTA and quantitative myocardial blood flow obtained from PET imaging can improve cardiac disease assessment. The HIT tool introduced in this paper may represent a significant advancement in the clinical use of this multimodal approach.

Internal carotid artery transposition as risk factor in pharyngeal surgery.

OBJECTIVE/HYPOTHESIS: Injuries to the internal carotid artery during simple pharyngeal surgical procedures can be catastrophic for the risk of massive bleeding. The aims of the study were 1) to report five cases of congenital and asymptomatic anomalies of the internal carotid artery with a review of the literature, 2) to assess the relationships between these anomalies and the possible risk in "routine" pharyngeal surgery, and 3) to determine the most accurate imaging techniques to evaluate these anomalies. STUDY DESIGN: Retrospective study of five patients with congenital anomalies of the internal carotid artery bulging the pharyngeal wall. METHODS Clinical records, pathology reports, and original imaging features of these kind of vascular lesions (computed tomography scans, three-dimensional time-of-flight magnetic resonance angiogram, and Doppler ultrasonography) were reviewed for each patient; vascular lesions were related to possible risk factors for pharyngeal surgery; and a review of the literature was made. RESULTS: All the patients were admitted for other diseases. The five anomalies, except one, were bulging the posterior pharyngeal wall and were asymptomatic. The peculiar literature referred 14 previous descriptions of similar anomalies. CONCLUSIONS: Some of the anomalies of the internal carotid artery can determine a bulge of the posterior pharyngeal wall. Because of the submucous position of the carotid artery at this level, such anomalies can constitute a risk factor for serious hemorrhage in routine surgical procedures that have become outpatient procedures and are often performed by inexperienced surgeons. The three-dimensional time-of-flight magnetic resonance angiogram together with Doppler ultrasonography were shown to be the most accurate imaging techniques to evaluate these anomalies.