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Gueugnon F.,French Institute of Health and Medical Research | Gueugnon F.,Center dEtude des Pathologies Respiratoires | Barascu A.,University of Tours | Barascu A.,Center dEtude des Pathologies Respiratoires | And 11 more authors.
Tumor Biology | Year: 2015

The KLK13 gene is dysregulated in several carcinomas, and its expression levels seem to be associated with disease prognosis. The aim of our study was to investigate the prognostic potential of KLK13 mRNA expression for patients with nonsmall cell lung cancer (NSCLC). Total RNA was isolated from cancerous and normal tissues from a cohort of 128 NSCLC patients. The KLK13 mRNA transcription levels were measured using a sensitive quantitative RT-PCR method. The results were normalized by dividing the KLK13 mRNA values with the geometric mean of mRNA expression from four reference genes: beta-actin, TATA-binding protein, hypoxanthine phosphoribosyltransferase 1, and acidic ribosomal phosphoprotein P0. The malignant tissues from the majority of patients (59.3 %) contained significantly more KLK13 mRNA transcripts than did the paired nonmalignant tissues (median difference 11.1-fold, P = 0.008). KLK13 was expressed at higher levels in females than that in males (P = 0.021). No other statistically significant association with clinicopathological data was observed. Kaplan-Meier survival analyses demonstrated that patients with KLK13-positive tumors survived significantly longer than those with KLK13-negative ones (P = 0.009). KLK13 expression was also shown to be able to stratify high-risk individuals among patients with early disease stages (P = 0.030). Multivariate Cox regression analysis showed that KLK13 expression is a favorable, independent prognostic indicator of overall survival (OS) (P = 0.024). Our results suggest that KLK13 mRNA expression constitutes a novel biomarker for the prediction of overall survival in NSCLC and that its quantitative assessment in tumor tissues can aid in treatment decision making. © 2015, International Society of Oncology and BioMarkers (ISOBM).

Kryza T.,Translational Research Institute | Kryza T.,Queensland University of Technology | Silva M.L.,Queensland University of Technology | Loessner D.,Queensland University of Technology | And 5 more authors.
Biochimie | Year: 2016

Cancer is the second leading cause of death with 14 million new cases and 8.2 million cancer-related deaths worldwide in 2012. Despite the progress made in cancer therapies, neoplastic diseases are still a major therapeutic challenge notably because of intra- and inter-malignant tumour heterogeneity and adaptation/escape of malignant cells to/from treatment. New targeted therapies need to be developed to improve our medical arsenal and counter-act cancer progression. Human kallikrein-related peptidases (KLKs) are secreted serine peptidases which are aberrantly expressed in many cancers and have great potential in developing targeted therapies. The potential of KLKs as cancer biomarkers is well established since the demonstration of the association between KLK3/PSA (prostate specific antigen) levels and prostate cancer progression. In addition, a constantly increasing number of in vitro and in vivo studies demonstrate the functional involvement of KLKs in cancer-related processes. These peptidases are now considered key players in the regulation of cancer cell growth, migration, invasion, chemo-resistance, and importantly, in mediating interactions between cancer cells and other cell populations found in the tumour microenvironment to facilitate cancer progression. These functional roles of KLKs in a cancer context further highlight their potential in designing new anti-cancer approaches. In this review, we comprehensively review the biochemical features of KLKs, their functional roles in carcinogenesis, followed by the latest developments and the successful utility of KLK-based therapeutics in counteracting cancer progression. © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Mathieu A.,CHRU de Tours | Mathieu A.,University of Tours | Guillon A.,University of Tours | Guillon A.,Center dEtude des Pathologies Respiratoires | And 6 more authors.
Journal of Neurosurgical Anesthesiology | Year: 2013

BACKGROUND: In patients with severe brain injury, endotracheal suctioning (ETS) can increase intracranial pressure (ICP) and reduce cerebral perfusion pressure (CPP). The aim of this prospective, blinded clinical trial was to assess the effectiveness of aerosolized lidocaine to prevent increase of ICP induced by ETS in mechanically ventilated head-injured patients. METHODS: First, we measured the particle size of aerosolized lidocaine produced by a vibrating plate nebulizer. Second, we measured the cerebral hemodynamic response to tracheal suctioning in patients in a neurosurgical intensive care unit with and without pretreatment of aerosolized lidocaine. RESULTS: Particle size distribution of aerosolized lidocaine was suitable to reach the bronchotracheal target during mechanical ventilation. In 15 patients included in this study, aerosolized lidocaine by itself did not induce significant changes in ICP. ETS caused an increase in ICP (variation: 6±2 mm Hg, P<0.05) with a concomitant decrease in CPP (variation: 2±2 mm Hg, P<0.05) that was maximal at 1 minute after NaCl aerosolization. This was prevented by aerosolization of lidocaine (variation of ICP: 1±1 mm Hg, and CPP: -1±1 mm Hg, P<0.05). CONCLUSIONS: Aerosolized lidocaine (2 mg/kg) can prevent ETS-induced increases in ICP, without modifying systemic and cerebral hemodynamics in deeply sedated patients. Copyright © 2012 by Lippincott Williams & Wilkins.

Guilleminault L.,Service de pneumologie et dexplorations fonctionnelles | Guilleminault L.,Center dEtude des Pathologies Respiratoires | Guilleminault L.,University of Tours | Carmier D.,Service de pneumologie et dexplorations fonctionnelles | And 6 more authors.
Revue de Pneumologie Clinique | Year: 2015

Despite recent advances in targeted therapy of non-small cell lung cancer (NSCLC), many patients do not benefit from these therapies. Inhibition of PD1/PDL1 is an interesting therapeutic target which restores the immune system against tumor cells. PD1 is located on lymphocytes and PDL1 on the antigen presenting cells. PD1 and PDL1 are co-inhibition molecules and their interaction results in immune tolerance against tumor cells. Anti-PD1 and anti-PDL1 antibodies have been developed to restore immune system in solid cancer including NSCLC. In phase I, studies assessing nivolumab, an anti-PD1 antibody, objective responses were observed in 13 to 18% of NSCLC patients failing previous treatment. The data obtained with anti-PDL1 antibodies is similar with objective responses ranging from 6 to 22%. The encouraging results of phase I/II studies must be confirmed in ongoing phase III studies. Anti-PD1 and anti-PDL1 antibodies exposed to new adverse events including auto-immune diseases whose support is not codified. Questions about treatment duration and criteria evaluation are not resolved. These treatments pave the way for immunomodulation in NSCLC treatment. © 2015 Elsevier Masson SAS.

Respaud R.,University of Tours | Vecellio L.,University of Tours | Vecellio L.,Center dEtude des Pathologies Respiratoires | Diot P.,University of Tours | And 3 more authors.
Expert Opinion on Drug Delivery | Year: 2015

Introduction: The pulmonary route is not invasive and can be used to target drugs directly to the lungs, limiting the exposure of secondary organs. It is, thus, an attractive alternative to the intravenous route, for the delivery of mAbs, which display limited transfer from blood into the lungs.Areas covered: This review provides an overview of the pharmacological properties of antibody-based treatments, describes those for respiratory diseases and discusses preclinical/clinical results of aerosolized antibody-based therapeutics. The advantages and limitations of aerosol devices and the formulation for the administration of aerosolized mAbs are also detailed.Expert opinion: Overall, the inhalation of mAbs for therapeutic purposes is both appropriate and feasible. The size and structure of the biotherapeutic molecule are important properties to be taken into account when trying to achieve long-term retention. Mesh nebulizers currently appear to be the most appropriate devices for the safe delivery of large amounts of active mAb into the lungs. mAbs should be formulated so as to prevent their degradation and possible immunogenicity. General guidelines can be given for mAb aerosolization, but the formulation and device combination should be adapted for each therapeutic and clinical application. © 2014 Informa UK, Ltd.

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