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Brellier F.,Friedrich Miescher Institute for Biomedical Research | Martina E.,Friedrich Miescher Institute for Biomedical Research | Martina E.,University of Basel | Martina E.,Harvard University | And 13 more authors.
BMC Clinical Pathology | Year: 2012

Background: Tenascins are large glycoproteins found in the extracellular matrix of many embryonic and adult tissues. Tenascin-C is a well-studied biomarker known for its high overexpression in the stroma of most solid cancers. Tenascin-W, the least studied member of the family, is highly expressed in the stroma of colon and breast tumors and in gliomas, but not in the corresponding normal tissues. Other solid tumors have not been analyzed. The present study was undertaken to determine whether tenascin-W could serve as a cancer-specific extracellular matrix protein in a broad range of solid tumors. Methods: We analyzed the expression of tenascin-W and tenascin-C by immunoblotting and by immunohistochemistry on multiple frozen tissue microarrays of carcinomas of the pancreas, kidney and lung as well as melanomas and compared them to healthy tissues. Results: From all healthy adult organs tested, only liver and spleen showed detectable levels of tenascin-W, suggesting that tenascin-W is absent from most human adult organs under normal, non-pathological conditions. In contrast, tenascin-W was detectable in the majority of melanomas and their metastases, as well as in pancreas, kidney, and lung carcinomas. Comparing lung tumor samples and matching control tissues for each patient revealed a clear overexpression of tenascin-W in tumor tissues. Although the number of samples examined is too small to draw statistically significant conclusions, there seems to be a tendency for increased tenascin-W expression in higher grade tumors. Interestingly, in most tumor types, tenascin-W is also expressed in close proximity to blood vessels, as shown by CD31 co-staining of the samples. Conclusions: The present study extends the tumor biomarker potential of tenascin-W to a broad range of solid tumors and shows its accessibility from the blood stream for potential therapeutic strategies. © 2012 Brellier et al.; licensee BioMed Central Ltd.


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.


Guilleminault L.,University of Tours | Guilleminault L.,Center dEtude des Pathologies Respiratoires | Azzopardi N.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Arnoult C.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | And 21 more authors.
Journal of Controlled Release | Year: 2014

Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream. © 2014 Elsevier B.V. All rights reserved.


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).


Respaud R.,CNRS Genetics, Immunotherapy, Chemistry & Cancer Laboratory | Respaud R.,University of Tours | March D.,Center dEtude des Pathologies Respiratoires | March D.,University of Tours | And 15 more authors.
mAbs | Year: 2014

Most monoclonal antibodies (mAbs) are administered to patients intravenously to ensure high bioavailability as rapidly as possible. The airways, however, are an attractive delivery route for mAbs for the treatment of lung diseases, making it possible to increase their concentration in the target organ while limiting their systemic passage. Several challenges must be overcome for translation into clinical practice. For example, the drug and device must be paired for the efficient and reliable deposition of a pharmacologically active and safe mAb in the lung region of interest. Mesh nebulizers appear to be the most effective aerosol-producing devices for delivering large amounts of biopharmaceutical while limiting protein instability during nebulization. We used metrological and analytic methods to analyze the effect of both antibody concentration and surfactant addition on aerosol performance and antibody integrity. These two factors had a limited effect on aerosol performance, but affected antibody aggregation. The addition of surfactants to antibody formulations at concentrations appropriate for lung administration markedly reduced the formation of medium or large aggregates, as shown by dynamic light scattering and fluorescence microscopy. Aggregation was also dependent on the type of mesh nebulizer, highlighting the need to optimize drug and device together. © 2014 Taylor & Francis Group, LLC.


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.


Herve V.,University of Tours | Herve V.,French Institute of Health and Medical Research | Herve V.,Center dEtude des Pathologies Respiratoires | Rabbe N.,University Pierre and Marie Curie | And 19 more authors.
mAbs | Year: 2014

K-ras mutations promote angiogenesis in lung cancer and contribute to the drug resistance of cancer cells. It is not clear whether K-ras mutated adenocarcinomas are sensitive to anti-angiogenic therapy with monoclonal antibodies (mAbs) that target vascular endothelial growth factor (VEGF). Anti-angiogenic mAbs are usually delivered systemically, but only a small proportion reaches the lung after intravenous injection. We investigated the relevance of a noninvasive pulmonary route for the delivery of anti-VEGF mAbs in the mouse K-rasLA1 model. We found that pulmonary delivery of these mAbs significantly reduced the number of tumor lesions and inhibited malignant progression. The antitumor effect involves the VEGFR2-dependent inhibition of blood vessel growth, which impairs tumor proliferation. Pharmacokinetic analysis of aerosolized anti-VEGF showed its low rate of passage into the bloodstream, suggesting that this delivery route is associated with reduced systemic side effects. Our findings highlight the value of the aerosol route for administration of anti-angiogenic mAbs in pulmonary adenocarcinoma with K-ras activating-mutations. © 2014 Taylor & Francis Group, LLC.


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.


Kryza T.,University of Tours | Kryza T.,Center dEtude des Pathologies Respiratoires | Lalmanach G.,Center dEtude des Pathologies Respiratoires | Lalmanach G.,French Institute of Health and Medical Research | And 13 more authors.
Biological Chemistry | Year: 2013

Kallikrein-12 (KLK12) may play an important role in angiogenesis modulating proangiogenic factor bioavailability and activating the kinin receptor B2 pathway. We studied whether KLK12 had an impact on angiogenesis and the activation of kinin receptor B2 results from the KLK12-dependent generation of kinins. KLK12 efficiently hydrolyzed high molecular weight kininogen, liberating a fragment containing the carboxy-terminal end of kinins. The kininogenase activity of KLK12 was poor, however, due to the cleavage resistance of the N-terminal side of the kinin sequence. A very low amount of kinins was accordingly released after in vitro incubation of high molecular weight kininogen with KLK12 and thus the proangiogenic activity of KLK12 in lung endothelial cells was not related to a kinin release. © 2013 by Walter de Gruyter Berlin Boston 2013.


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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