The development of more effective, better tolerated drug treatments for progressive pulmonary fibrosis (of which idiopathic pulmonary fibrosis is the most common and severe form) is a research ...priority. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is a key regulator of inflammation and fibrosis and therefore represents a potential therapeutic target. However, the use of synthetic PPAR-γ agonists may be limited by their potentially severe adverse effects. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, we have demonstrated that the non-racemic selective PPAR-γ modulator GED-0507 is able to reduce body weight loss, ameliorate clinical and histological features of pulmonary fibrosis, and increase survival rate without any safety concerns. Here, we focused on the biomolecular effects of GED-0507 on various inflammatory/fibrotic pathways. We demonstrated that preventive and therapeutic administration of GED-0507 reduced the BLM-induced mRNA expression of several markers of fibrosis, including transforming growth factor (TGF)-β, alpha-smooth muscle actin, collagen and fibronectin as well as epithelial-to-mesenchymal transition (EMT) and expression of mucin 5B. The beneficial effect of GED-0507 on pulmonary fibrosis was confirmed in vitro by its ability to control TGFβ-induced myofibroblast activation in the A549 human alveolar epithelial cell line, the MRC-5 lung fibroblast line, and primary human lung fibroblasts. Compared with the US Food and Drug Administration-approved antifibrotic drugs pirfenidone and nintedanib, GED-0507 displayed greater antifibrotic activity by controlling alveolar epithelial cell dysfunction, EMT, and extracellular matrix remodeling. In conclusion, GED-0507 demonstrated potent antifibrotic properties and might be a promising drug candidate for the treatment of pulmonary fibrosis.
The ileal mucosa of Crohn disease (CD) patients is abnormally colonized by adherent-invasive E. coli (AIEC) that are able to adhere to and invade intestinal epithelial cells. Here, we show that ...CD-associated AIEC strains adhere to the brush border of primary ileal enterocytes isolated from CD patients but not controls without inflammatory bowel disease. AIEC adhesion is dependent on type 1 pili expression on the bacterial surface and on carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression on the apical surface of ileal epithelial cells. We report also that CEACAM6 acts as a receptor for AIEC adhesion and is abnormally expressed by ileal epithelial cells in CD patients. In addition, our in vitro studies show that there is increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma or TNF-alpha stimulation and after infection with AIEC bacteria, indicating that AIEC can promote its own colonization in CD patients.
Repertoire-based learning is a data-efficient adaptation approach based on a two-step process in which (1) a large and diverse set of policies is learned in simulation, and (2) a planning or learning ...algorithm chooses the most appropriate policies according to the current situation (e.g., a damaged robot, a new object, etc.). In this paper, we relax the assumption of previous works that a single repertoire is enough for adaptation. Instead, we generate repertoires for many different situations (e.g., with a missing leg, on different floors, etc.) and let our algorithm selects the most useful prior. Our main contribution is an algorithm, APROL (Adaptive Prior selection for Repertoire-based Online Learning) to plan the next action by incorporating these priors when the robot has no information about the current situation. We evaluate APROL on two simulated tasks: (1) pushing unknown objects of various shapes and sizes with a robotic arm and (2) a goal reaching task with a damaged hexapod robot. We compare with "Reset-free Trial and Error" (RTE) and various single repertoire-based baselines. The results show that APROL solves both the tasks in less interaction time than the baselines. Additionally, we demonstrate APROL on a real, damaged hexapod that quickly learns to pick compensatory policies to reach a goal by avoiding obstacles in the path.
Natural history of eosinophilic gastroenteritis Pineton de Chambrun, Guillaume; Gonzalez, Florent; Canva, Jean-Yves ...
Clinical gastroenterology and hepatology,
11/2011, Letnik:
9, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Eosinophilic gastroenteritis (EGE) is a rare gastrointestinal disorder; little is known about its natural history. We determined the clinical features and long-term outcomes of patients with EGE.
We ...reviewed files from 43 patients diagnosed with EGE who were followed from January 1988 to April 2009. The diagnosis was made according to standard criteria after other eosinophilic gastrointestinal disorders were excluded. We analyzed data on initial clinical presentation and long-term outcomes.
EGE was classified as mucosal, subserosal, or muscular in 44%, 39%, and 12% of cases, respectively. Disease location was mostly duodenal (62%), ileal (72%), or colonic (88%); it was less frequently esophageal (30%) or gastric (38%). Blood eosinophilia (numbers >500/mm(3)) was observed in 74% of cases. Spontaneous remission occurred in 40% of patients; the majority of treated patients (74%) received oral corticosteroids, which were effective in most cases. After a median follow-up period of 13 years (0.8-29 years), we identified 3 different courses of disease progression: 18 patients (42%; 9 with subserosal disease) had an initial flare of the disease without relapse, 16 (37%) had multiple flares that were separated by periods of full remission (recurring disease), and 9 (21%) had chronic disease.
The clinical presentation of EGE is heterogeneous and varies in histologic pattern; about 40% of patients resolve the disease spontaneously, without relapse. Approximately 50% have a more complex disease, which is characterized by unpredictable relapses and a chronic course.
Intestinal fibrosis is mainly associated with Crohn's disease and is defined as a progressive and excessive deposition of extracellular matrix components. No specific antifibrotic therapies are ...available. In this study, we evaluate the antifibrotic effect of a novel 5-ASA analog able to activate the peroxisome proliferator-activated receptor γ, named GED-0507-34 Levo.
Colonic fibrosis was induced in 110 C57BL/6 mice by 3 cycles of 2.5% (wt/vol) dextran sulfate sodium administration for 6 weeks. The preventive effects of oral daily GED (30 mg · kg(-1) · d(-1)) administration were evaluated using a macroscopic and histological score and also through biological endpoints. Expression of main markers of myofibroblasts activation was determined in transforming growth factor (TGF-β)-stimulated intestinal fibroblasts and epithelial cells.
GED improved macroscopic and microscopic intestinal lesions in dextran sulfate sodium-treated animals and reduced the profibrotic gene expression of Acta2, COL1a1, and Fn1 by 1.48-folds (P < 0.05), 1.93-folds (P < 0.005), and 1.03-fold (P < 0.05), respectively. It reduced protein levels of main markers of fibrosis (α-SMA and Collagen I-II) and the main TGF-β/Smad pathway components. GED also decreased the interleukin-13 and connective tissue growth factor expression by 1.89-folds (P < 0.05) and 2.2-folds (P < 0.005), respectively. GED inhibited TGF-β-induced activation of both fibroblast and intestinal epithelial cell lines, by regulating mRNA expression of α-SMA and fibronectin, and restoring the TGF-β-induced loss of intestinal epithelial cell markers. GED treatment also reduced the TGF-β and ACTA1 expression in primary human intestinal fibroblasts from ulcerative colitis patients.
GED ameliorates intestinal fibrosis in dextran sulfate sodium-induced chronic colitis in mice and regulates major profibrotic cellular and molecular mechanisms.
Introduction
The aim of this study was to evaluate the association between serum ustekinumab (UST) trough levels and response to induction and maintenance UST treatment in refractory Crohn’s Disease ...(CD) patients.
Methods
We performed a prospective study including CD patients who received UST from September 2015 to January 2017. Patients received 90 mg of UST subcutaneously at weeks 0, 4, and 12, then every 8 weeks. Two cohorts of patients were analyzed: an induction cohort and a maintenance cohort. We evaluated clinical, biological, and imaging/endoscopic response to UST treatment. UST trough levels and anti-UST antibodies were dosed at weeks 12 and 28 in the induction cohort, and at a single time point in the maintenance cohort.
Results
Forty-nine patients were enrolled in the maintenance cohort. Mean concentrations of UST were 1.88 ± 1.40 µg/mL. UST trough levels were not significantly different in patients with or without clinical, biological, or imaging/endoscopic responses to UST treatment (
p
> 0.11). Twenty-three consecutive patients were included in the induction cohort. At week 12, mean UST concentrations were 1.45 ± 1.15 µg/mL. Patients with a biological response to UST treatment had significant higher serum UST trough concentration (median 1.72 µg/mL) than non-responders (median 0.56 µg/mL,
p
= 0.02). A UST trough level ≥ 1.10 µg/mL at week 12 was associated with a biological response to UST treatment at 6 months.
Conclusion
UST trough levels were associated with a biological response at the end of the induction phase. In patients with low levels of UST, optimization treatment may be necessary to obtain a sustained response.
Intestinal fibrosis is characterized by abnormal production and deposition of extracellular matrix (ECM) proteins by activated myofibroblasts. The main progenitor cells of activated myofibroblasts ...are the fibroblasts and the epithelial cells, the latter through the epithelial-mesenchymal transition (EMT).
To evaluate the action of the new PPAR-γ modulator, GED-0507-34 Levo (GED) on the expression of EMT associated and regulatory proteins such as TGF-β, Smad3, E-cadherin, Snail, ZEB1, β-catenin, and GSK-3β, in a mouse model of DSS-induced intestinal fibrosis.
Chronic colitis and fibrosis were induced by oral administration of 2.5% DSS (w/v) for 6 weeks. GW9662 (GW), a selective PPAR-γ inhibitor, was also administered by intraperitoneal injection at the dose of 1 mg/kg/day combined with GED treatment. All drugs were administered at the beginning of the second cycle of DSS (day 12). 65 mice were randomly divided into five groups (H2O as controls n = 10, H2O+GED n = 10, DSS n = 15, DSS+GED n = 15, DSS+GED+GW n = 15). The colon was excised for macroscopic examination and histological and morphometric analyses. The level of expression of molecules involved in EMT and fibrosis, like TGF-β, Smad3, E-cadherin, Snail, ZEB1, β-catenin, GSK-3β and PPAR-γ, was assessed by immunohistochemistry, immunofluorescence, western blot and Real Time PCR.
GED improved the DSS-induced chronic colitis and fibrosis. GED was able to reduce the expression of the main fibrosis markers (α-SMA, collagen I-III and fibronectin) as well as the pivotal pro-fibrotic molecules IL-13, TGF-β and Smad3, while it increased the anti-fibrotic PPAR-γ. All these GED effects were nullified by co-administration of GW with GED. Furthermore, GED was able to normalize the expression levels of E-cadherin and β-catenin and upregulated GSK-3β, that are all known to be involved both in EMT and fibrosis.
The DSS-induced intestinal fibrosis was improved by the new PPAR-γ modulator GED-0507-34 Levo through the modulation of EMT mediators and pro-fibrotic molecules and through GSK-3β induction.
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