Arginase 1 expression is increased during hepatic stellate cell activation and facilitates collagen synthesis

Activation of hepatic stellate cells (HSC) is a key event in the initiation of liver fibrosis. Activated HSCs proliferate and secrete excessive amounts of extracellular matrix (ECM), disturbing liver architecture and function, leading to fibrosis and eventually cirrhosis. Collagen is the most abundant constituent of ECM and proline is the most abundant amino acid of collagen. Arginine is the precursor in the biosynthetic pathway of proline. Arginine is the exclusive substrate of both nitric oxide synthase (NOS) and arginase. NOS is an M1 (proinflammatory) marker of macrophage polarization whereas arginase-1 (Arg1) is an M2 (profibrogenic) marker of macrophage polarization. Differential expression of NOS and Arg1 has not been studied in HSCs yet. To identify the expression profile of arginine catabolic enzymes during HSC activation and to investigate their role in HSC activation, primary rat HSCs were cultured-activated for 7 days and expression of iNOS and Arg1 were investigated. Nor-NOHA was used as a specific and reversible arginase inhibitor. During HSC activation, iNOS expression decreased whereas Arg1 expression increased. Inhibition of Arg1 in activated HSCs efficiently inhibited collagen production but not cell proliferation. HSC activation is accompanied by a switch of arginine catabolism from iNOS to Arg1. Inhibition of Arg1 decreases collagen synthesis. Therefore, we conclude that Arg1 can be a therapeutic target for the inhibition of liver fibrogenesis.</p

Towards Auditory Profile-Based Hearing-Aid Fittings:BEAR Rationale and Clinical Implementation

(1) Background: To improve hearing-aid rehabilitation, the Danish ‘Better hEAring Rehabilitation’ (BEAR) project recently developed methods for individual hearing loss characterization and hearing-aid fitting. Four auditory profiles differing in terms of audiometric hearing loss and supra-threshold hearing abilities were identified. To enable auditory profile-based hearing-aid treatment, a fitting rationale leveraging differences in gain prescription and signal-to-noise (SNR) improvement was developed. This report describes the translation of this rationale to clinical devices supplied by three industrial partners. (2) Methods: Regarding the SNR improvement, advanced feature settings were proposed and verified based on free-field measurements made with an acoustic mannikin fitted with the different hearing aids. Regarding the gain prescription, a clinically feasible fitting tool and procedure based on real-ear gain adjustments were developed. (3) Results: Analyses of the collected real-ear gain and SNR improvement data confirmed the feasibility of the clinical implementation. Differences between the auditory profile-based fitting strategy and a current ‘best practice’ procedure based on the NAL-NL2 fitting rule were verified and are discussed in terms of limitations and future perspectives. (4) Conclusion: Based on a joint effort from academic and industrial partners, the BEAR fitting rationale was transferred to commercially available hearing aids

Efficacy evaluation of surgery combined with chemotherapy for stage IIIA small cell lung cancer patients: a retrospective analysis

Background: The efficacy of surgery in combination of chemotherapy for stage IIIA small cell lung cancer (IIIA-SCLC) is controversial. The aim of the present study was to analyze the efficacy of surgery combined with chemotherapy, especially in the setting of neoadjuvant chemotherapy (NAC) followed by surgery for IIIA-SCLC.Methods: Between 2004 and 2015, we reviewed 2,199 chemotherapy-treated stage IIIA (N1/2) SCLC cases in the Surveillance, Epidemiology, and End Results (SEER) database, and 32 NAC + intentional radical resection treated, centrally-located IIIA-SCLC cases at Shanghai Pulmonary Hospital (SPH). Outcomes were compared between surgically and non-surgically treated patients from the SEER database after propensity score matching (PSM), and comparing lobectomy/bi-lobectomy and pneumonectomy patients from SPH. Prognostic factors were evaluated by Kaplan-Meier method and the Cox proportional hazards regression model.Results: There was significantly higher overall survival (OS) in surgically treated IIIA-SCLC patients (OS, 44.8 vs. 21.2 months, P=0.048), and similar efficacy was observed between sub-lobectomy and lobectomy/ bi-lobectomy patients (OS: 55.6 vs. 30.3 months, P=0.167) in SEER database. At SPH, significantly higher OS was associated with T1 stage (before NAC: T1 vs. T2-4, 48.7 vs. 32.2 months, P=0.025; after NAC: T1 vs. T2-4, 42.7 vs. 21.3 months, P=0.048). Female sex [hazard ratio (HR): 0.078, P=0.009], T1 stage (HR: 13.048, P=0.026), and pneumonectomy (HR: 0.095, P=0.009) were independent prognostic factors for IIIASCLC patients who received NAC + intentional radical resection.Conclusions: For stage IIIA SCLC patients, complete resection combined with chemotherapy might improve the prognosis than patients without surgery. Post-NAC lobectomy was not found to be superior to sub-lobectomy, while pneumonectomy was considered suitable for central-type IIIA-SCLC patients after NAC treatment

Continuous NPWT regulates fibrosis in murine diabetic wound healing

Scarring is associated with significant morbidity. The mechanical signaling factor yes-associated protein (YAP) has been linked to Engrailed-1 (En1)-lineage positive fibroblasts (EPFs), a pro-scarring fibroblast lineage, establishing a connection between mechanotransduction and fibrosis. In this study, we investigate the impact of micromechanical forces exerted through negative pressure wound therapy (NPWT) on the pathophysiology of fibrosis. Full-thickness excisional dorsal skin wounds were created on diabetic (db/db) mice which were treated with occlusive covering (control) or NPWT (continuous, -125 mmHg, 7 days; NPWT). Analysis was performed on tissue harvested 10 days after wounding. NPWT was associated with increased YAP