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Korfei M.,Justus Liebig University | Schmitt S.,Institute of Biochemistry | Ruppert C.,Justus Liebig University | Henneke I.,Justus Liebig University | And 12 more authors.
Journal of Proteome Research | Year: 2011

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which no effective therapy exists to date. To identify the molecular mechanisms underlying IPF, we performed comparative proteome analysis of lung tissue from patients with sporadic IPF (n = 14) and human donor lungs (controls, n = 10) using two-dimensional gel electrophoresis and MALDI-TOF-MS. Eighty-nine differentially expressed proteins were identified, from which 51 were up-regulated and 38 down-regulated in IPF. Increased expression of markers for the unfolded protein response (UPR), heat-shock proteins, and DNA damage stress markers indicated a chronic cell stress-response in IPF lungs. By means of immunohistochemistry, induction of UPR markers was encountered in type-II alveolar epithelial cells of IPF but not of control lungs. In contrast, up-regulation of heat-shock protein 27 (Hsp27) was exclusively observed in proliferating bronchiolar basal cells and associated with aberrant re-epithelialization at the bronchiolo-alveolar junctions. Among the down-regulated proteins in IPF were antioxidants, members of the annexin family, and structural epithelial proteins. In summary, our results indicate that IPF is characterized by epithelial cell injury, apoptosis, and aberrant epithelial proliferation. © 2011 American Chemical Society. Source


Conroy T.,Institut Universitaire de France | Galais M.-P.,Center Francois Baclesse | Raoul J.-L.,Center Eugene Marquis | Bouche O.,Center Hospitalier University Robert Debre | And 13 more authors.
The Lancet Oncology | Year: 2014

Background: Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer. Methods: We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I-IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0-2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m2 per day for 4 days and cisplatin 75 mg/m2 on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094. Findings: 134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9-36·4). Median progression-free survival was 9·7 months (95% CI 8·1-14·5) in the FOLFOX group and 9·4 months (8·1-10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70-1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil-cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin-fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group. Interpretation: Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery. Funding: UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer. © 2014 Elsevier Ltd. Source


Abdulmalak C.,Center Hospitalier University du Bocage | Cottenet J.,University Hospital | Beltramo G.,Center Hospitalier University du Bocage | Georges M.,Center Hospitalier University du Bocage | And 10 more authors.
European Respiratory Journal | Year: 2015

Haemoptysis is a serious symptom with various aetiologies. Our aim was to define the aetiologies, outcomes and associations with lung cancer in the entire population of a high-income country. This retrospective multicentre study was based on the French nationwide hospital medical information database collected over 5 years (2008-2012). We analysed haemoptysis incidence, aetiologies, geographical and seasonal distribution and mortality. We studied recurrence, association with lung cancer and mortality in a 3-year follow-up analysis. Each year, ∼15000 adult patients (mean age 62 years, male/female ratio 2/1) were admitted for haemoptysis or had haemoptysis as a complication of their hospital stay, representing 0.2% of all hospitalised patients. Haemoptysis was cryptogenic in 50% of cases. The main aetiologies were respiratory infections (22%), lung cancer (17.4%), bronchiectasis (6.8%), pulmonary oedema (4.2%), anticoagulants (3.5%), tuberculosis (2.7%), pulmonary embolism (2.6%) and aspergillosis (1.1%). Among incident cases, the 3-year recurrence rate was 16.3%. Of the initial cryptogenic haemoptysis patients, 4% were diagnosed with lung cancer within 3 years. Mortality rates during the first stay and at 1 and 3 years were 9.2%, 21.6% and 27%, respectively. This is the first epidemiological study analysing haemoptysis and its outcomes in an entire population. Haemoptysis is a life-threatening symptom unveiling potentially life-threatening underlying conditions. © ERS 2015. Source


Ortega-Deballon P.,Center Hospitalier University du Bocage | Radais F.,Center Hospitalier University du Bocage | Facy O.,Center Hospitalier University du Bocage | D'Athis P.,University du Bocage | And 5 more authors.
World Journal of Surgery | Year: 2010

Background Nowadays, most patients who undergo colorectal surgery are discharged early. An early predictor of septic complications could avoid readmissions and decrease morbidity. CRP could be a good predictor allowing a safe discharge. Methods A prospective, observational study was conducted from November 2007 to October 2008. All patients who underwent elective colorectal surgery were included. Clinical (temperature, pulse, abdominal tenderness, bowel movements) and laboratory data (C-reactive protein, leukocyte count) were recorded and evaluated as early predictors of septic complications (namely, anastomotic leaks). All detected leaks were considered fistulas, independently of their clinical significance. Clinical and inflammatory parameters were analyzed with univariate and multivariate techniques; logistic regression was performed and areas under the receiver operating characteristic curve were compared. Results A total of 133 patients were included. The overall incidence of anastomotic leaks was 15.5% and mortality was 4.5%. C-reactive protein at postoperative days 2 and 4 was a good predictor of anastomotic leak (areas under the curve were 0.715 and 0.845, respectively) and other postoperative septic complications (areas under the curve were 0.804 and 0.787), showing the highest accuracy among clinical and laboratory data. A cutoff of 125 mg/l in the level of C-reactive protein at postoperative day 4 yielded a sensitivity of 81.8% and a negative predictive value of 95.8% for the detection of anastomotic leakage. Conclusions C-reactive protein is a simple way to ensure a safe discharge from hospital after elective colorectal surgery. Patients with CRP values >125 mg/l on the fourth postoperative day should not be discharged. © Societe Internationale de Chirurgie 2010. Source


Petit J.-M.,University of Burgundy | Petit J.-M.,Center Hospitalier University du Bocage | Guiu B.,University of Burgundy | Guiu B.,Center Hospitalier University du Bocage | And 15 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: Recently, it has been shown in the general population that an allele in the adiponutrin (PNPLA3) gene was strongly associated with increased liver fat content (LFC), independently of visceral adiposity and insulin resistance. Objective: In this study,weset out to determine whether LFC, evaluated using 1H-MR spectroscopy, was associated with PNPLA3 rs738409 polymorphism in people with type 2 diabetes. We also evaluated the influence of this polymorphism on the relationship between LFC and either visceral adiposity or carotid intima media thickness (CIMT). Design, Settings, and Participants: A total of 218 type 2 diabetic patients were included in this study. Main Outcome Measures: LFC, area of visceral fat, and CIMT were measured. Results: A total of 139 (63.7%) patients had steatosis. The rs738409 minor G allele was associated with LFC. The number of patients with steatosis was significantly higher among minor G allele carriers in comparison to C allele homozygote carriers (70.3 vs. 57.2%; P = 0.04) In the subgroup of C allele homozygote carriers, LFC correlated with body mass index (r = 0.27; P = 0.003) and visceral fat area (r=0.30; P=0.002), but not with CIMT. In the subgroup of minor G allele carriers, LFC correlated inversely with CIMT (r = -0.23; P = 0.03), but not with body mass index or with visceral fat area. In multivariate logistic regression, the relationship between the highest quartile of CIMT and steatosis was different according to adiponutrin polymorphism. Conclusions: This study confirms that in people with type 2 diabetes, LFC is related to rs738409 polymorphism.Thelack of a relationship with visceral obesityandthe inverse correlation with CIMT suggest that fatty liver associated with the minor G allele of the PNPLA3 rs738409 polymorphism may not be linked to metabolic disorders. Copyright © 2010 by The Endocrine Society. Source

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